Heterocyclic mitochondrial activity inhibitors and uses thereof

ABSTRACT

Heterocyclic compounds of Formula I:and pharmaceutically acceptable salt thereof are disclosed. The use of such heterocyclic compounds and pharmaceutically acceptable salt thereof for the treatment of cancers, and more particularly cancers sensitive to mitochondrial activity inhibition and increased reactive oxygen species (ROS) levels, is also disclosed. Such cancers include acute myeloid leukemia (AML), preferably AML characterized by certain features, such as high level of expression of one or more Homeobox (HOX)-network genes, high and/or low expression of specific genes, the presence of one or more cytogenetic or molecular risk factors such as intermediate cytogenetic risk, Normal Karyotype (NK), mutated NPM1, mutated CEBPA, mutated FLT3, mutated DNMT3A, mutated TET2, mutated IDH1, mutated IDH2, mutated RUNX1, mutated WT1, mutated SRSF2, intermediate cytogenetic risk with abnormal karyotype (intern(abnK)), trisomy 8 (+8) and/or abnormal chromosome (5/7), and/or a high leukemic stem cell (LSC) frequency.

RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.16/761,210, filed May 1, 2020 which claims the benefit of U.S.Provisional Application No. 62/581,239 filed on Nov. 3, 2017 and toCanadian application No. 2,995,617 filed on Feb. 16, 2018, the contentsof which are incorporated herein by reference in their entirety for allpurposes.

TECHNICAL FIELD

The present disclosure generally relates to the inhibition ofmitochondrial activity, for example for the treatment of cancers such asacute myeloid leukemia (AML), and more specifically of AML subtypestypically associated with poor prognosis.

BACKGROUND

Accumulating evidence suggests that mitochondrial bioenergetics,biosynthesis and signaling are involved in tumorigenesis. For example,the anti-diabetic drugs metformin and phenformin, which inhibitmitochondrial ETC complex I, have been shown to inhibit tumor growth invarious cancers including lung, lymphoma, and breast cancers. In breastcancer cells, metformin and phenformin reduces tricarboxylic acid (TCA)cycle intermediate production through complex I inhibition (Janzer A, etal. Proc Natl Acad Sci USA. 2014; 111:10574-10579). Mitochondria producereactive oxygen species (ROS) as a natural by-product of electrontransport chain (ETC) activity. Some anticancer drugs are generators ofROS, inductors of oxidative stress and initiators of apoptosis in thecells. ROS, which include free radicals such as superoxide (O₂ ⁻),hydroxyl radical (HO⁻) and hydrogen peroxide (H₂O₂) are often generatedfollowing inhibition of the mitochondrial ETC (Li et al., 2003. J. Biol.Chem. 278, 8516-8525; Muller et al., 2004. J. Biol. Chem. 279,49064-49073), and leads to tumor cell death at least in part throughautophagy-induced cell death (Chen et al., Journal of Cell Science 2007120: 4155-4166). Thus, targeting mitochondrial activity/metabolism,notably to increase ROS levels in tumor cells, constitutes a promisingapproach for cancer therapy.

Acute Myeloid Leukemia (AML) is a particularly lethal form of cancer,with most patients dying within two years of diagnosis. It is one of theleading causes of death among young adults. AML is a collection ofneoplasms with heterogeneous pathophysiology, genetics and prognosis.Mainly based on cytogenetics and molecular analysis, AML patients arepresently classified into groups or subsets of AML with markedlycontrasting prognosis. Approximately 45% of all AML patients arecurrently classified into distinct groups with variable prognosis basedon the presence or absence of specific recurrent cytogeneticabnormalities.

Targeting FLT3 receptor tyrosine kinases with FLT3 tyrosine kinaseinhibitors (TKIs) has shown encouraging results in the treatment ofFLT3-mutated AML (generally associated with poor clinical outcome), butin most patients, responses are incomplete and not sustained. Also, theinduction of acquired resistance to TKIs has emerged as a clinicalproblem.

Also, inhibitors of other pathologically activated kinases in AML suchas c-KIT and JAK2 have achieved only rare bone marrow responses.

There is a need for the identification of novel therapeutic strategiesfor the treatment of cancers, including AML such as AML associated withpoor prognosis.

SUMMARY

According to one aspect, the present technology generally relates tocompounds of Formula I or pharmaceutically acceptable salts thereof:

-   -   wherein:    -   X¹ represents —N═, —CH═, or —O—;    -   X² represents —CH═, —C(R²)═, or a covalent bond;    -   X³ represents —CH═, —C(R²)═, or a covalent bond;    -   X⁴ represents —O—, —C(R³)═, —N═, or —S—;    -   X⁵ represents a covalent bond, —C(R³)═, or —O—;    -   provided that one of X² and X³ is —C(R²)═ and the other of X²        and X³ is —CH═ or a covalent bond, and provided that at most        only one of X², X³, and X⁵ represents a covalent bond;    -   R² represents ArylC(R³)═C(H)—, HeteroarylC(R³)═C(H)—,        ArylN(R³)C(O)—, HeteroarylN(R³)C(O)—, Arylcyclopropyl-,        Heteroarylcyclopropyl-, R³OC(O)C(H)═C(H)—, R³OC(O)—, Aryl-C═C—,        Heteroaryl-C≡C—, Aryl-, Heteroaryl-, Aryl-CH(R³)—CH(R³)—, or        Heteroaryl-CH(R³)—CH(R³)—, wherein the Aryl group and the        Heteroaryl group are optionally substituted with one to three R⁴        groups, which are the same or different;    -   R³ independently in each occurrence represents —H, —C₁-C₅alkyl,        —C₂-C₅alkenyl, —C₂-C₅alkynyl, —C₁-C₄fluoroalkyl, or        —C₃-C₇cycloalkyl, the alkyl, alkenyl, alkynyl, and cycloalkyl        being optionally substituted with —OR⁶, —N(R⁶)₂, —C(O)OR⁶, —CN        or —C(O)N(R⁶)₂;    -   R⁴ independently in each occurrence represents —F, —Cl, —Br, —I,        —SR³, —SOR⁵, —S(O)₂R⁵, —S(O)₂N(R³)₂, -triazolyl, —CN, —C(O)OR³,        —C(O)R³, —NO₂, —C(O)N(R³)₂, —OR³, —C(R³)₂OH, —N(R³)₂,        —N(R³)C(O)R³, —N(R³)C(O)OR⁵, —OC(O)N(R³)₂, —N₃, —R³,

-   -   R⁵ independently in each occurrence represents —H, —C₁-C₅alkyl,        —C₂-C₅alkenyl, —C₂-C₅alkynyl, —C₁-C₄fluoroalkyl, or        —C₃-C₇cycloalkyl, the alkyl, alkenyl, alkynyl, and cycloalkyl        being optionally substituted with —OR⁶, —N(R⁶)₂, —C(O)OR⁶, —CN        or —C(O)N(R⁶)₂;    -   R⁶ independently represents —H, —C₁-C₅alkyl, —C₂-C₅alkenyl,        —C₂-C₅alkynyl, —C₁-C₄fluoroalkyl, or —C₃-C₇cycloalkyl;    -   L¹ represents —CHR³—O—, —CH₂—NH—, —C(O)NH—, —C(O)—CHR⁶,        —CR⁶═CR⁶—, —CH₂—S—, —CH₂—, or —CH₂—O—CH₂—; X⁶ and X⁷        independently represent —CR³═, or —N═;    -   L² represents a covalent bond, —C(O)—, —C(R³)(OH)—, —O—, —S—,        —CHR³—, —CH(R³)—S—, or —CH(R³)—O—; m independently in each        occurrence represents an integer from 1 to 4;    -   p represents an integer from 1 to 6; and    -   R¹ represents heteroaryl, aryl, —N₃, —OH, —OC(O)N(R⁷)₂,        —C(O)N(R⁷)₂, —N(R⁷)₂, —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁸,        —N(R⁷)C(O)-L³-OR⁷, or —N(R⁷)C(O)-L³-OC(O)N(R⁷)₂, the heteroaryl        and aryl being optionally substituted with one or more R⁹, which        are the same or different, wherein:    -   L³ represents C₁-C₅alkylene, C₂-C₅alkenylene, C₂-C₅alkynylene,        or C₁-C₄fluoroalkylene, the alkylene, alkenylene, and alkynylene        being optionally substituted with one or more R⁹, which are the        same or different;    -   R⁷ independently represents —H, —C₁-C₅alkyl, —C₂-C₅alkenyl,        —C₂-C₅alkynyl, —C₁-C₄fluoroalkyl, or —C₃-C₇cycloalkyl; the        alkyl, alkenyl, alkynyl, and cycloalkyl being optionally        substituted with one or more R⁹, which are the same or        different,    -   or when two R⁷ groups are attached to a same nitrogen atom, the        two R⁷ groups together with the nitrogen atom to which they are        attached optionally form a 5-7-membered heterocycloalkyl, the        heterocycloalkyl optionally comprising one or more further        heteroatom independently selected from —O—, —N(R³)—, —S—, —S(O)—        and —SO₂—, the heterocycloalkyl being optionally substituted        with one or more R⁹, which are the same or different;    -   R⁸ independently represents —H, —C₁-C₅ alkyl, —C₂-C₅alkenyl,        —C₂-C₅alkynyl, —C₁-C₄fluoroalkyl, or —C₃-C₇cycloalkyl; the        alkyl, alkenyl, alkynyl, and cycloalkyl being optionally        substituted with one or more R⁹, which are the same or        different; and    -   R⁹ independently represents —C₁-C₆alkyl, —C₃-C₆alkyl-OR¹¹,        —C₃-C₆cycloalkyl, —C₃-C₆cycloalkyl-OR¹¹, —C₁-C₆alkyl- OC(O)R¹¹,        —C₁-C₅ alkyl-OC(O)N(R¹¹)₂, —C₁-C₆alkyl-OC(O)N(R¹¹)-L⁴-OR¹¹,        —C₃-C₆alkyl-C(O)OR¹¹, —C₃-C₆alkyl-C(O)N(R¹¹)₂, —C₁-C₅        alkyl-N(R¹¹)₂, —C₁-C₅ alkyl-N(R¹¹)C(O)R¹¹,        —C₁-C₆alkyl-N(R¹¹)C(O)-L⁴-N(R¹¹)—C(O)R¹¹,        —C₁-C₆alkyl-N(R¹¹)S(O)₂R¹⁰, —C₁-C₅        alkyl-N(R¹¹)S(O)₂-L⁴-N(R¹¹)—C(O)OR¹⁰, —Si(C₁-C₅alkyl)₃,        —C(O)—O—C₁-C₆alkyl, phenyl optionally substituted with R⁴,        benzyl optionally substituted with R⁴, pyridinyl optionally        substituted with R⁴, or

-   -   wherein:    -   L⁴ represents C₁-C₅alkylene, C₂-C₅alkenylene, C₂-C₅alkynylene,        or C₁-C₄fluoroalkylene; and    -   R¹⁰ independently represents —H, —C₁-C₅alkyl, —C₂-C₅alkenyl,        —C₂-C₅alkynyl, —C₁-C₄fluoroalkyl, or —C₃-C₇cycloalkyl, the        alkyl, alkenyl, alkylnyl, and cycloalkyl being optionally        substituted with —OR⁶, —N(R⁶)₂, —C(O)OR⁶, —CN or —C(O)N(R⁶)₂;    -   R¹¹ independently represents —H, —C₁-C₅alkyl, —C₂-C₅alkenyl,        —C₂-C₅alkynyl, —C₁-C₄fluoroalkyl, or —C₃-C₇cycloalkyl, the        alkyl, alkenyl, alkylnyl, and cycloalkyl being optionally        substituted with —OR⁶, —N(R⁶)₂, —C(O)OR⁶, —CN or —C(O)N(R⁶)₂, or    -   when two R¹¹ groups are attached to a same nitrogen atom, the        two R¹¹ groups together with the nitrogen atom to which they are        attached optionally form a 5-7-membered heterocycloalkyl, the        heterocycloalkyl optionally comprising one or more further        heteroatom independently selected from —O—, —N(R³)—, —S—, —S(O)—        and —SO₂ ⁻.

According to one embodiment, in the compounds of Formula I, groups R⁵,R⁸ and R¹⁰ are each other than —H. Other embodiments of the compounds,taken alone or in combination are as defined hereinbelow.

In another aspect, the present application relates to the use of acompound as herein defined, or a pharmaceutically acceptable saltthereof, for treating acute myeloid leukemia (AML) in a subject.Inversely, the application relates to a compound, or pharmaceuticallyacceptable salt thereof, as herein defined for use in the treatment ofacute myeloid leukemia (AML). Alternatively, this application relates tothe use of a compound as herein defined, or a pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for treatingacute myeloid leukemia (AML) in a subject. In a further aspect, theapplication relates to a method for treating acute myeloid leukemia(AML), said method comprising administering to a subject in need thereofan effective amount of a compound as herein defined, or apharmaceutically acceptable salt thereof. For instance, the subject is apediatric subject. Alternatively, the subject is an adult subject.

In one embodiment, the AML is poor prognosis AML. In another embodiment,the AML comprises at least one of the following features: (a) high levelof expression of one or more homeobox (HOX)-network genes; (b) highlevel of expression of one or more of the genes depicted in Table 1; (c)low level of expression of one or more of the genes depicted in Table 2;(d) one or more of the following cytogenetic or molecular risk factor:intermediate cytogenetic risk, Normal Karyotype (NK), mutated NPM1,mutated CEBPA, mutated FLT3, mutated DNA methylation genes, mutatedRUNX1, mutated WT1, mutated SRSF2, intermediate cytogenetic risk withabnormal karyotype (intern(abnK)), trisomy 8 (+8) and abnormal chr(5/7);and (e) a leukemic stem cell (LSC) frequency of at least about 1 LSC per1×10⁶ total cells. For instance, the AML comprises high level ofexpression of one or more HOX-network genes, e.g., the one or moreHOX-network genes being HOXB1, HOXB2, HOXB3, HOXB5, HOXB6, HOXB7, HOXB9,HOXB-A53, HOXA1, HOXA2, HOXA3, HOXA4, HOXA5, HOXA6, HOXA7, HOXA9,HOXA10, HOXA10-A5, HOXA11, HOXA11-AS, MEIS1 and/or PBX3. For example,the one or more HOX-network genes are HOXA9 and/or HOXA10.

In another embodiment, the AML comprises high level of expression of oneor more of the genes depicted in Table 1 hereinbelow. In furtherembodiment, the AML comprises low level of expression of one or more ofthe genes depicted in Table 2. In yet another embodiment, the AMLcomprises one or more of the cytogenetic or molecular risk factordefined in item (d) above, for instance, AML is intermediate cytogeneticrisk AML and/or NK-AML, and/or AML comprises at least two of saidcytogenetic or molecular risk factors, or at least three of saidcytogenetic or molecular risk factors.

In a further embodiment, the AML comprises a mutated NPM1, a mutatedFLT3 and/or a mutated DNA methylation gene e.g., DNMT3A or IDH1. Inanother embodiment, the AML comprises a mutated NPM1, a mutated FLT3 anda mutated DNA methylation gene, preferably the DNA methylation genebeing DNMT3A. For example, the mutated FLT3 is FLT3 with internal tandemduplication (FLT3-ITD).

In yet another embodiment, the AML comprises an LSC frequency of atleast about 1 LSC per 1×10⁶ total cells, or an LSC frequency of at leastabout 1 LSC per 5×10⁵ total cells. In a further embodiment, the AMLcomprises at least two of the above features (a) to (e), or at leastthree of features (a) to (e). In another embodiment, the AML is NK-AMLwith mutated NPM1.

According to another aspect, in the use, compound for use or method asdefined herein, the compound, or pharmaceutically acceptable saltthereof, is present in a pharmaceutical composition.

In a further aspect, the present description relates to a method fordetermining the likelihood that a subject suffering from acute myeloidleukemia (AML) responds to a treatment with the compound orpharmaceutically acceptable salt thereof as defined herein, said methodcomprising determining whether AML cells from said subject comprise atleast one of the features defined above, wherein the presence of said atleast one of the following features in said AML cells is indicative thatthe subject has a high likelihood of responding to said treatment.

Additional objects and features of the present compound, compositions,methods and uses will become more apparent upon reading of the followingnon-restrictive description of exemplary embodiments, which should notbe interpreted as limiting the scope of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-D show the link between expression of HOX-network genes and AMLprognosis. FIG. 1A: Identification of patient samples with consistenthigh expression of HOX-network gene members (black, upper right of eachgraph) and with consistent low expression of HOX-network gene members(grey, lower left of each graph) in the prognostic Leucegene AML cohort(263 AML patients) studied herein, a cohort of AML patients for whichsufficient information is available to make survival studies. Values inbrackets indicate the range of expression of each gene. FIG. 1B: Overallsurvival of AML patients belonging to HOX-network high (lower line,n=100) versus low (upper line, n=27) subgroups.

FIG. 1C: Identification of a HOXA9/HOXA10 high AML sample population.FIG. 1D: Overall survival of AML patients belonging to the HOXA9/HOXA10high group (lower line, n=131) and HOXA9/HOXA10 med/low group (upperline, n=132). In FIG. 1B and FIG. 1D, p-values were determined bylog-rank test. Abbreviations: AML: Acute myeloid leukemia; HOX:Homeobox; ME/S1: ME/S Homeobox 1; RPKM: Reads Per Kilobase per Millionmapped reads; Std: standard deviation.

FIGS. 2A-H show the characterization of the pharmacological response ofHOX-high AML cells. FIG. 2A: Overview of the primary screen workflow of60 compounds (Table 4). HOXA9 and HOXA10 were used as representativegenes for the distinction between HOX-high (dark grey, n=131) versusHOX-med/low (light grey, n=132) patient samples. FIG. 2B: Summary of theresults of the primary screen leading to the identification ofMubritinib as a candidate drug targeting HOX-high AML patient cells. Thehorizontal dashed line corresponds to p=0.05 and the vertical dashedline indicate a 2.5-fold difference in EC₅₀ values. FIG. 2C: AML patientsamples included in the validation screen comprising HOX-high (darkgrey, upper right) and HOX-med/low (light grey) specimens. FIG. 2D:Differential EC₅₀ values in HOX-high versus HOX-med/low AML samplesmeasured in the validation screen. The p-value was determined byMann-Whitney test. FIG. 2E: Frequencies of Mubritinib EC₅₀ valuesmeasured in 200 different AML specimens define Mubritinib-sensitive(EC₅₀<375 nM, n=100) and Mubritinib-resistant (EC₅₀≥375 nM, n=100)groups. Normal primitive CD34-positive cord blood cells were moderatelysensitive to Mubritinib (EC₅₀>375 nM). FIG. 2F: Differential overallsurvival of patients belonging to the Mubritinib-sensitiveversus-resistant groups. The p-value was determined by log-rank test.

FIG. 2G: Transcriptomic profiles of Mubritinib-sensitive versusMubritinib-resistant specimens, highlighting an overexpression ofHOX-network genes. FIG. 2H: Transcriptomic profiles ofMubritinib-sensitive versus Mubritinib-resistant specimens, highlightingmost differentially expressed genes (criteria: log (fold change)>0.8(=6-fold), RPKM>0.1). Abbreviations: AML: Acute myeloid leukemia;ANKRD18B: Ankyrin Repeat Domain 18B; BEND6: BEN Domain Containing 6;COL4A5: Collagen Type IV Alpha 5; FDR: False Discovery Rate; HOX:Homeobox; KIRREL: Kin Of IRRE Like; LINC: Long Non Coding; LSC: leukemicstem cell; ME/S1: MEIS Homeobox 1; MIR: Micro RNA; MSLN: Mesothelin;NKX2.3: NK2 Homeobox 3; P13K: Phosphatidylinositol-4,5-bisphosphate3-kinase; PPBP: Pro-Platelet Basic Protein; PRDM16: PR/SET Domain 16;PRG3: Proteoglycan 3; RPKM: Reads Per Kilobase per Million mapped reads;RTK: receptor tyrosine kinase; S100A16: S100 Calcium Binding ProteinA16; SNORD: Small Nucleolar RNA; ST18: Suppression Of Tumorigenicity 18,Zinc Finger; ZNF: Zinc Finger Protein.

FIGS. 3A-H show a characterization of Mubritinib-sensitive AML specimensaccording to various genetic and clinical features. FIG. 3A: MubritinibEC₅₀ values according to cytogenetic risk classes. FIG. 3B: Mutationsenriched in highly-sensitive Mubritinib AML specimens (EC₅₀<100 nM,n=59) versus Mubritinib highly-resistant AML specimens (EC₅₀>1 μM, n=58)according to a Bonferroni corrected exact Fisher's test. FIG. 3C:Mubritinib EC₅₀ values according to the presence of mutated genes. FIG.3D: Mubritinib EC₅₀ values according to the genetic subgroups. FIG. 3E:Summary of Mubritinib-sensitive patient sample characteristics. FIG. 3F:EC₅₀ values of poor prognostic patient specimens carrying mutations (m)in NPM1, FLT3-ITD and DNMT3A (Papaemmanuil, E. et al. N Engl J Med 374,2209-2221) versus other AML samples. FIG. 3G-H: Leukemic stem cell (LSC)frequencies in Mubritinib sensitive versus resistant groups of patientsamples belonging to the normal karyotype (NK) subgroup (FIG. 3G) and tothe NK subgroup carrying mutated NPM1 (NPM1m) (FIG. 3H). In FIGS. 3D-H,p-values were calculated by Mann-Whitney test. Horizontal lines in allpanels indicate median values. Abbreviations: AML: Acute myeloidleukemia; AbnChr: abnormal chromosome; ASXL1: Additional Sex Combs Like1, Transcriptional Regulator; CEBPA: CCAAT/Enhancer Binding ProteinAlpha; Complex: complex karyotype; DNMT3A: DNA(Cytosine-5-)-Methyltransferase 3 Alpha; EVI1: Ecotropic ViralIntegration Site 1; FLT3: Fms Related Tyrosine Kinase 3; HOX: Homeobox;IDH: Isocitrate Dehydrogenase (NADP(+)); Inter(AbnK): intermediatecytogenetic risk with abnormal karyotype; m; mutated; MLL: Mixed LineageLeukemia 1; NK: normal karyotype; NPM1: Nucleophosmin (NucleolarPhosphoprotein B23, Numatrin); NRAS: Neuroblastoma RAS Viral OncogeneHomolog; NUP98: Nucleoporin 98 kDa; RUNX1: Runt Related TranscriptionFactor 1; SRSF2: Serine/Arginine-Rich Splicing Factor 2; TET2: TetMethylcytosine Dioxygenase 2; TP53: Tumor Protein P53; WT1: Wilms Tumor1; +8: trisomy 8.

FIGS. 4A-4G show the results on experiments assessing the effect ofMubritinib on tumor cells. FIG. 4A: Number of viable (Propidium idodide(PI)-negative) cells after four days of treatment of OCI-AML3 withdifferent concentrations of Mubritinib. FIG. 4B: Fold-enrichment inPI-positive cells (dead cells) compared to DMSO-treated cells after 27hours of treatment of OCI-AML3 with different concentrations ofMubritinib. FIG. 4C: Percentage of early apoptotic and late apoptoticcells in OCI-AML3 cells after 24 hours of treatment with control DMSO,100 nM or 10 μM Mubritinib. FIG. 4D: AML patients' cell sensitivity toMubritinib versus Lapatinib ditosylate, an ERBB2 inhibitor. FIG. 4E:OCI-AML3 dose response curves after treatment with Mubritinib or withtwo known ERBB2 inhibitors: Lapatinib ditosylate or Sapitinib. FIG. 4F:ERBB2 gene expression in Mubritinib-sensitive versusMubritinib-resistant patient samples. FIG. 4G: ERBB2 protein expressionversus isotype control in ERBB2 over-expressing BT474 breast cancer cellline and in OCI-AML3 Mubritinib-sensitive AML cell line measured by flowcytometry. Samples were either treated with Mubritinib at 2 μM for 24hours or mock-treated with DMSO. Abbreviations: AML: Acute myeloidleukemia; ERBB2: Erb-B2 Receptor Tyrosine Kinase 2; FITC: Fluoresceinisothiocyanate; PE: Phycoerythrin; Pos: positive.

FIGS. 5A-5J show the results on experiments assessing the mode of actionof Mubritinib for mediating tumor cell death.

FIG. 5A: OCI-AML3 leukemic cells were either pre-incubated for 4 hourswith 6 mM N-acetyl-cysteine (NAC), a reactive oxygen species (ROS)scavenger, or with vehicle (water) before being treated with 100 nMMubritinib for 24 h or vehicle (DMSO). Cells underwent apoptotic deathupon Mubritinib treatment as assessed by Annexin V and propidium iodide(PI) staining by flow cytometry. Mubritinib-induced cell death wasreduced when cells were cultured in the presence of NAC. FIG. 5B: Flowcytometric staining using 2′,7′-dichlorofluorescin diacetate (DCFDA), afluorogenic dye that measures hydroxyl, peroxyl and other ROS activitywithin the cell, showing that Mubritinib treatment (500 nM, 24 h)induces ROS activity in OCI-AML3 leukemic cells. FIGS. 5C and 5D showthe levels of reduced and oxidized levels of glutathione, respectively,in OCI-AML3 treated or not with Mubritinib, as detected by liquidchromatography-mass spectrometry (LC/MS). FIG. 5E shows the results ofexperiments assessing the effect of Mubritinib (1 μM) on oxygenconsumption rate (OCR) in OCI-AML3 leukemic cells, as measured using aSeahorse XF® extracellular flux analyzer (Agilent®). FIG. 5F shows theresults of experiments assessing the effect of Mubritinib on themitochondrial electron transfer chain (ETC) complex I (pivotal formitochondrial respiration/activity), as measured using a cell free assay(MitoTox™ Complex I OXPHOS activity microplate assay, Abcam). FIG. 5G isa graph depicting dose-response curves upon Mubritinib treatment (6-dayculture assay in 384-well plates) of OCI-AML3 and OCI-AML5 cell lines.FIGS. 5H-J are graphs depicting dose-response curves following treatmentof OCI-AML3 and OCI-AML5 cell lines with other ETC inhibitors, namelyOligomycin (inhibitor of complex V, FIG. 5H), Rotenone (inhibitor ofcomplex I, FIG. 5I) and Deguelin (inhibitor of complex I, FIG. 5J).

FIGS. 6A-6E are graphs showing the effects of Mubritinib treatment onthe levels of different intermediates of the citric acid cycle inOCI-AML3 cells, namely citrate (FIG. 6A), alpha-ketoglutarate (FIG. 6B),succinate (FIG. 6C), fumarate (FIG. 6D), and malate (FIG. 6E).

FIG. 7 is a graph showing the inhibitory effects of Mubritinib andMetformin hydrochloride on AML specimens. 20 AML specimens were testedfor sensitivity to Mubritinib and Metformin hydrochloride at 1 μM inleukemic stem cell activity conservative culture conditions (Pabst etal., 2014, Nature Methods 11(4):436-42).

FIGS. 8A and 8B are graphs showing the effect of Mubritinib on Complex Ienzyme activity (diaphorase-type activity) in OCI-AML3 cells, asassessed using the Complex I Enzyme Activity Microplate Assay Kitaccording to the manufacturer's instructions (Abcam, catalog No.ab109721). Complex I activity is determined by following the oxidationof NADH to NAD+ and the simultaneous reduction of a dye which leads toincreased absorbance at OD=450 nm. FIG. 8A: Effect on Complex Iubiquitone-dependent activity. FIG. 8B: Effect on Complex Iubiquitone-independent activity.

FIG. 9 is a schematic representation of the putative mechanism of actionof Mubritinib for inducing tumor cell death.

DETAILED DESCRIPTION

All technical and scientific terms and expressions used herein have thesame definitions as those commonly understood by a person skilled in theart to which the present technology pertains. The definition of someterms and expressions used is nevertheless provided below. To the extentthe definitions of terms in the publications, patents, and patentapplications incorporated herein by reference are contrary to thedefinitions set forth in this specification, the definitions in thisspecification will control. The section headings used herein are fororganizational purposes only, and are not to be construed as limitingthe subject matter disclosed.

i. Definitions

Chemical structures described herein are drawn according to conventionalstandards. Also, when an atom, such as a carbon atom, as drawn seems toinclude an incomplete valency, then the valency is assumed to besatisfied by one or more hydrogen atoms even though these are notnecessarily explicitly drawn. Hydrogen atoms should be inferred to bepart of the compound. Herein, in case of discrepancy between a chemicalname and a chemical structure, the chemical structure prevails.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting. It should be notedthat, the singular forms “a”, “an”, and “the” include plural forms aswell, unless the content clearly dictates otherwise. Thus, for example,reference to a composition containing “a compound” also contemplates amixture of two or more compounds. It should also be noted that the term“or” is generally employed in its sense including “and/or” unless thecontent clearly dictates otherwise. Throughout this specification,unless the context requires otherwise, the words “comprise,” “comprises”and “comprising” will be understood to imply the inclusion of a statedstep or element or group of steps or elements but not the exclusion ofany other step or element or group of steps or elements. Furthermore, tothe extent that the terms “including”, “includes”, “having”, “has”,“with”, or variants thereof are used in either the detailed descriptionand/or the claims, such terms are intended to be inclusive in a mannersimilar to the term “comprising”.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext.

The use of any and all examples, or exemplary language (“e.g.”, “suchas”) provided herein, is intended merely to better illustrate theinvention and does not pose a limitation on the scope of the inventionunless otherwise claimed.

The term “about” or “approximately” means within an acceptable errorrange for the particular value as determined by one of ordinary skill inthe art, which will depend in part on how the value is measured ordetermined, i.e., the limitations of the measurement system. Forexample, “about” can mean within 1 or more than 1 standard deviation,per the practice in the art. Alternatively, “about” can mean a range ofup to 20%, preferably up to 10%, more preferably up to 5%, and morepreferably still up to 1% of a given value. Alternatively, particularlywith respect to biological systems or processes, the term can meanwithin an order of magnitude, preferably within 5-fold, and morepreferably within 2-fold, of a value. Where particular values aredescribed in the application and claims, unless otherwise stated theterm “about” meaning within an acceptable error range for the particularvalue should be assumed.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure when applicable; forexample, the R and S configurations for each asymmetric center.Therefore, single stereochemical isomers as well as enantiomeric,diastereomeric, and geometric (or conformational) mixtures of thepresent compounds are within the scope of the present description. Thetherapeutic compound unless otherwise noted, also encompasses allpossible tautomeric forms of the illustrated compound, if any. The termalso includes isotopically labeled compounds where one or more atomshave an atomic mass different from the atomic mass most abundantly foundin nature. Examples of isotopes that may be incorporated into thepresent compounds include, but are not limited to, ²H (D), ³H (T), ¹¹C,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, any one of the isotopes of sulfur, etc. Thecompound may also exist in unsolvated forms as well as solvated forms,including hydrated forms. The compound may exist in multiple crystallineor amorphous forms. In general, all physical forms are equivalent forthe uses contemplated herein and are intended to be within the scope ofthe present invention.

The expression “pharmaceutically acceptable salt” refers to those saltsof the compounds of the present description which are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof humans and lower animals without undue toxicity, irritation, allergicresponse and the like, and are commensurate with a reasonablebenefit/risk ratio. Pharmaceutically acceptable salts are well known inthe art. For example, S. M. Berge, et al. describes pharmaceuticallyacceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19(1977).

The term “solvate” refers to a physical association of one of thepresent compound with one or more solvent molecules, including water andnon-aqueous solvent molecules. This physical association may includehydrogen bonding. In certain instances, the solvate will be capable ofisolation, for example when one or more solvent molecules areincorporated in the crystal lattice of a crystalline solid. The term“solvate” encompasses both solution-phase and isolable solvates.Exemplary solvates include, without limitation, hydrates, hemihydrates,ethanolates, hemiethanolates, n-propanolates, iso-propanolates,1-butanolates, 2-butanolate, and solvates of other physiologicallyacceptable solvents, such as the Class 3 solvents described in theInternational Conference on Harmonization (ICH), Guide for Industry, Q3CImpurities: Residual Solvents (1997). Accordingly, the compound asherein described also includes each of its solvates and mixturesthereof.

Herein a general chemical structure, such as Formula (I), with varioussubstituents (R¹ to R¹¹, X¹ to X⁷, etc.) and various radicals (alkyl,heteroring, etc.) enumerated for these substituents is intended to serveas a shorthand method of referring individually to each and everymolecule obtained by the combination of any of the radicals for any ofthe substituents. Each individual molecule is incorporated into thespecification as if it were individually recited herein. Further, allsubsets of molecules within the general chemical structures are alsoincorporated into the specification as if they were individually recitedherein.

Similarly, a list of several elements, such as Compounds 1, 2, 3, etc.,is intended to describe the ensemble of all elements listed as well aseach individual element, which is thus incorporated into thespecification as if it were individually recited herein. Further, allsubsets of these listed elements are also incorporated into thespecification as if they were individually recited herein.

Herein, the terms “alkyl”, “alkylene”, “alkenyl”, “alkenylene”,“alkynyl”, “alkynylene” and their derivatives (such as alkoxy,alkyleneoxy, etc.) have their ordinary meaning in the art. For morecertainty: alkyl is a monovalent saturated aliphatic hydrocarbon radicalof general formula C_(n)H_(2n+1) but may still be used in somecircumstances to designate a multivalent group (e.g., an alkylene);alkenyl is a monovalent aliphatic hydrocarbon radical similar to analkyl, but comprising at least one double bond; alkynyl is a monovalentaliphatic hydrocarbon radical similar to an alkyl, but comprising atleast one triple bond; alkylene is a bivalent saturated aliphatichydrocarbon radical of general formula—C_(n)H_(2n)—(also calledalkanediyl); alkenylene is a bivalent aliphatic hydrocarbon radicalsimilar to an alkylene, but comprising at least one double bond;alkynylene is a bivalent aliphatic hydrocarbon radical similar to analkylene, but comprising at least one triple bond; alkyloxy or alkoxy isa monovalent radical of formula —O-alkyl; alkyleneoxy is a bivalentradical of formula —O-alkylene (e.g., alkyleneoxy is —O—CH₂—CH₂, whichis called ethyleneoxy, where a linear chain comprising two or moreethyleneoxy groups attached together (i.e. —O—CH₂—CH₂-]_(n)-) can bereferred to as a polyethylene glycol (PEG), polyethylene oxide (PEO), orpolyoxyethylene (POE) chain; alkenyloxy is a monovalent radical offormula —O-alkenyl; alkenyleneoxy is a bivalent radical of formula—O-alkenylene-; alkynyloxy is a monovalent radical of formula—O-alkynyl; and alkynyleneoxy is a bivalent radical of formula—O-alkynylene. It is to be noted that, unless otherwise specified, thehydrocarbon chains of the above groups can be linear or branched.Further, unless otherwise specified, these groups can contain between 1and 18 carbon atoms, more specifically between 1 and 12 carbon atoms,between 1 and 6 carbon atoms, between 1 and 3 carbon atoms, or contain 1or 2, or 1 carbon atom, or 2 carbon atoms.

Herein, the terms “cycloalkyl”, “aryl”, “heterocycloalkyl”, and“heteroaryl” have their ordinary meaning in the art. For more certainty:aryl is a monovalent aromatic hydrocarbon radical presenting adelocalized conjugated r system, most commonly an arrangement ofalternating single and double bonds, between carbon atoms arranged inone or more rings, wherein the rings can be fused (i.e. share two ringatoms), for example naphthalene, or linked together through a covalentbond, for example biphenyl, or linked together through a radical thatallow continuation of the delocalized conjugated r system between therings (e.g., —C(═O)—, —NRR—), for example benzophenone; heteroaryl is anaryl wherein at least one of the ring carbon atoms is replaced by aheteroatom, such as nitrogen or oxygen, where examples of heteroarylinclude monocyclic or fused rings as well as and multiple rings linkedtogether through a radical that allow continuation of the delocalizedconjugated r system between the rings (e.g., —C(═O)—, —NRR—), such asindole-5-carbonylbenzene; cycloalkyl is a monovalent saturated aliphatichydrocarbon radical of general formula C_(n)H_(2n−1), wherein the carbonatoms are arranged in one or more rings (also called cycles) which maybe spiro, fused or bridged; heterocycloalkyl is a cycloalkyl wherein atleast one of the carbon atoms is replaced by a heteroatom.

Of note, term “heteroring” encompasses both non-aromatic (i.e.,aliphatic), either saturated rings (i.e. heterocycloalkyls) or ringswith one or more double and/or triple covalent bond(heterocycloalkenyls, heterocycloalkynyls, and heterocycloalkenynyls) aswell as heteroaryls.

It is to be noted that, unless otherwise specified, the ring(s) of theabove groups can each comprise between 4 and 8 ring atoms, preferablybetween 5 or 6 ring atoms. Also, unless otherwise specified, the abovegroups may preferably comprise one or more rings, preferably 1 or 2rings, more preferably a single ring.

Examples of heteroaryl include thienyl, furanyl (furyl), pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, 3H-indolyl,indolinyl, isoindolyl, indolizinyl, benzothienyl (benzothiophenyl),benzofuranyl, isobenzofuranyl, dibenzofuranyl, indazolyl,benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl,pyrrolopyridinyl (e.g., pyrrolo[3,2-b]pyridinyl orpyrrolo[3,2-c]pyridinyl), pyrazolopyridinyl (e.g.,pyrazolo[1,5-a]pyridinyl), furopyridinyl, purinyl, imidazopyrazinyl(e.g., imidazo[4,5-b]pyrazinyl), quinolyl (quinolinyl), isoquinolyl(isoquinolinyl), quinolonyl, isoquinolonyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, naphthyridinyl, andpteridinyl carbazolyl, acridinyl, phenanthridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one.

Herein, the term “heteroatom” means nitrogen, oxygen, sulfur (includingwhen in —SO₂—), phosphorus, preferably nitrogen or oxygen.

The terms “subject” and “patient” are used interchangeably herein, andrefer to an animal, preferably a mammal, most preferably a human. In anembodiment, the patient is an adult cancer (e.g., AML) patient. In anembodiment, the patient is less than 60 years old. In anotherembodiment, the patient is 60 years old or older. In another embodiment,the AML patient is a pediatric cancer (e.g., AML) patient.

Terms and symbols of genetics, molecular biology, biochemistry andnucleic acid used herein follow those of standard treatises and texts inthe field, e.g., Green and Sambrook, Molecular Cloning: A LaboratoryManual, 4^(th) Edition, 2012 (Cold Spring Harbor Laboratory Press);Ausubel et al., Current Protocols in Molecular Biology (2001 and laterupdates thereto); Kornberg and Baker, DNA Replication, Second Edition (WUniversity Science Books, 2005); Lehninger, Biochemistry, sixth Edition(W H Freeman & Co (Sd), New York, 2012); Strachan and Read, HumanMolecular Genetics, Second Edition (Wiley-Liss, New York, 1999);Eckstein, editor, Oligonucleotides and Analogs: A Practical Approach(Oxford University Press, New York, 1991); Gait, editor, OligonucleotideSynthesis: A Practical Approach (IRL Press, Oxford, 1984); and the like.All terms are to be understood with their typical meanings establishedin the relevant art.

Any and all combinations and subcombinations of the embodiments andfeatures disclosed herein are also contemplated. For example, theexpression of any combination of 2, 3, 4, 5 or more of the genesidentified herein may be used in the methods described herein.

Recitation of ranges of values herein are merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range, unless otherwise indicated herein, and eachseparate value is incorporated into the specification as if it wereindividually recited herein. All subsets of values within the ranges arealso incorporated into the specification as if they were individuallyrecited herein.

In the studies described herein, it is shown that AML cells expressinghigh levels of HOX-network genes, which are associated with poorprognosis/survival, are sensitive to the heterocyclic compoundMubritinib. Mubritinib-sensitive AML cells were also shown to beenriched in AML samples having certain features, such as for exampleoverexpression or underexpression of specific genes, certain cytogeneticor molecular risk factors, such as Normal Karyotype (NK), mutated NPM1,FLT3-ITD and DNMT3A specimens, and in specimens having high leukemicstem cell (LSC) frequencies. It is also demonstrated that Mubritinib,characterized as an inhibitor of the tyrosine kinase human epidermalgrowth factor receptor 2 (HER2/ErbB2), does not target this protein inAML cells, and compelling evidence that Mubritinib induces AML cellapoptosis through inhibition of mitochondrial activity/respiration, moreparticularly of the ETC, resulting in increased ROS production insensitive AML cells, are provided. Based on these results, severalheterocyclic compounds structurally related to Mubritinib were developedand shown to inhibit the growth of the tumor cell lines OCI-AML3 andMLL-AF9.

ii. Heterocyclic Compounds

The present description relates to the use of heterocyclic compoundsstructurally related to Mubritinib and their pharmaceutically acceptablesalts, for example for the treatment of cancers, such as leukemia,including AML and more particularly Mubritinib-sensitive AML subtypesare described below. Several of the compounds described herein arenovel, so the present disclosure also relates to these compounds orpharmaceutically acceptable thereof per se, i.e., independently fromtheir use.

Examples of heterocyclic compounds are illustrated by general Formula I:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X¹ represents —N═, —CH═, or —O—;    -   X² represents —CH═, —C(R²)═, or a covalent bond;    -   X³ represents —CH═, —C(R²)═, or a covalent bond;    -   X⁴ represents —O—, —C(R³)═, —N═, or —S—; and    -   X⁵ represents a covalent bond, —C(R³)═, or —O—;    -   provided that one of X² and X³ is —C(R²)═ and the other of X²        and X³ is —CH═ or a covalent bond, and provided that at most        only one of X², X³, and X⁵ represents a covalent bond;    -   R² represents ArylC(R³)═C(H)—, HeteroarylC(R³)═C(H)—,        ArylN(R³)C(O)—, HeteroarylN(R³)C(O)—, Arylcyclopropyl-,        Heteroarylcyclopropyl-, R³OC(O)C(H)═C(H)—, R³OC(O)—, Aryl-C≡C—,        Heteroaryl-C≡C—, Aryl-, Heteroaryl-, Aryl-CH(R³)—CH(R³)—, or        Heteroaryl-CH(R³)—CH(R³)—, wherein the Aryl group and the        Heteroaryl group are optionally substituted with one to three R⁴        groups, which are the same or different;    -   R³ independently in each occurrence represents —H, —C₁-C₅alkyl,        —C₂-C₅alkenyl, —C₂-C₅alkynyl, —C₁-C₄fluoroalkyl, or        —C₃-C₇cycloalkyl, the alkyl, alkenyl, alkynyl, and cycloalkyl        being optionally substituted with —OR⁶, —N(R⁶)₂, —C(O)OR⁶, —CN        or —C(O)N(R⁶)₂;    -   R⁴ independently in each occurrence represents —F, —Cl, —Br, —I,        —SR³, —SOR⁵, —S(O)₂R⁵, —S(O)₂N(R³)₂, -triazolyl, —CN, —C(O)OR³,        —C(O)R³, —NO₂, —C(O)N(R³)₂, —OR³, —C(R³)₂OH, —N(R³)₂,        —N(R³)C(O)R³, —N(R³)C(O)OR⁵, —OC(O)N(R³)₂, —N₃, —R³,

-   -   R⁵ independently in each occurrence represents —H, —C₁-C₅alkyl,        —C₂-C₅alkenyl, —C₂-C₅alkynyl, —C₁-C₄fluoroalkyl, or        —C₃-C₇cycloalkyl, the alkyl, alkenyl, alkynyl, and cycloalkyl        being optionally substituted with —OR⁶, —N(R⁶)₂, —C(O)OR⁶, —CN        or —C(O)N(R⁶)₂;    -   R⁶ independently represents —H, —C₁-C₅alkyl, —C₂-C₅alkenyl,        —C₂-C₅alkynyl, —C₁-C₄fluoroalkyl, or —C₃-C₇cycloalkyl;    -   L¹ represents —CHR³—O—, —CH₂—NH—, —C(O)NH—, —C(O)—CHR⁶,        —CR⁶═CR⁶—, —CH₂—S—, —CH₂—, or —CH₂—O—CH₂—; X⁶ and X⁷        independently represent —CR³═, or —N═;    -   L² represents a covalent bond, —C(O)—, —C(R³)(OH)—, —O—, —S—,        —CHR³—, —CH(R³)—S—, or —CH(R³)—O—; m independently in each        occurrence represents an integer from 1 to 4;    -   p represents an integer from 1 to 6; and    -   R¹ represents heteroaryl, aryl, —N₃, —OH, —OC(O)N(R⁷)₂,        —C(O)N(R⁷)₂, —N(R⁷)₂, —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁸,        —N(R⁷)C(O)-L³-OR⁷, or —N(R⁷)C(O)-L³-OC(O)N(R⁷)₂, the heteroaryl        and aryl being optionally substituted with one or more R⁹, which        are the same or different, wherein:    -   L³ represents C₁-C₅alkylene, C₂-C₅alkenylene, C₂-C₅alkynylene,        or C₁-C₄fluoroalkylene, the alkylene, alkenylene, and alkynylene        being optionally substituted with one or more R⁹, which are the        same or different;    -   R⁷ independently represents —H, —C₁-C₅ alkyl, —C₂-C₅alkenyl,        —C₂-C₅alkynyl, —C₁-C₄fluoroalkyl, or —C₃-C₇cycloalkyl; the        alkyl, alkenyl, alkynyl, and cycloalkyl being optionally        substituted with one or more R⁹, which are the same or        different,    -   or when two R⁷ groups are attached to a same nitrogen atom, the        two R⁷ groups together with the nitrogen atom to which they are        attached optionally form a 5-7-membered heterocycloalkyl, the        heterocycloalkyl optionally comprising one or more further        heteroatom independently selected from —O—, —N(R³)—, —S—, —S(O)—        and —SO₂—, the heterocycloalkyl being optionally substituted        with one or more R⁹, which are the same or different;    -   R⁸ independently represents —H, —C₁-C₅ alkyl, —C₂-C₅alkenyl,        —C₂-C₅alkynyl, —C₁-C₄fluoroalkyl, or —C₃-C₇cycloalkyl; the        alkyl, alkenyl, alkynyl, and cycloalkyl being optionally        substituted with one or more R⁹, which are the same or        different; and    -   R⁹ independently represents —C₁-C₅ alkyl, —C₀-C₆alkyl-OR¹¹,        —C₃-C₆cycloalkyl, —C₃-C₆cycloalkyl-OR¹¹, —C₁-C₆alkyl- OC(O)R¹¹,        —C₁-C₆alkyl-OC(O)N(R¹¹)₂, —C₁-C₆alkyl-OC(O)N(R¹¹)-L⁴-OR¹¹,        —C₃-C₆alkyl-C(O)OR¹¹, —C₃-C₆alkyl-C(O)N(R¹¹)₂, —C₁-C₅        alkyl-N(R¹¹)₂, —C₁-C₅ alkyl-N(R¹¹)C(O)R¹¹, —C₁-C₅        alkyl-N(R¹¹)C(O)-L⁴-N(R¹¹)—C(O)R¹¹, —C₁-C₆alkyl-N(R¹¹)S(O)₂R¹⁰,        —C₁-C₅ alkyl-N(R¹¹)S(O)₂-L⁴-N(R¹¹)—C(O)OR¹⁰, —Si(C₁-C₅alkyl)₃,        —C(O)—O—C₁-C₅ alkyl, phenyl optionally substituted with R⁴,        benzyl optionally substituted with R⁴, pyridinyl optionally        substituted with R⁴, or

-   -   wherein:    -   L⁴ represents C₁-C₅alkylene, C₂-C₅alkenylene, C₂-C₅alkynylene,        or C₁-C₄fluoroalkylene; and    -   R¹⁰ independently represents —H, —C₁-C₅alkyl, —C₂-C₅alkenyl,        —C₂-C₅alkynyl, —C₁-C₄fluoroalkyl, or —C₃-C₇cycloalkyl, the        alkyl, alkenyl, alkylnyl, and cycloalkyl being optionally        substituted with —OR⁶, —N(R⁶)₂, —C(O)OR⁶, —CN or —C(O)N(R⁶)₂;    -   R¹¹ independently represents —H, —C₁-C₅alkyl, —C₂-C₅alkenyl,        —C₂-C₅alkynyl, —C₁-C₄fluoroalkyl, or —C₃-C₇cycloalkyl, the        alkyl, alkenyl, alkylnyl, and cycloalkyl being optionally        substituted with —OR⁶, —N(R⁶)₂, —C(O)OR⁶, —CN or —C(O)N(R⁶)₂, or    -   when two R¹¹ groups are attached to a same nitrogen atom, the        two R¹¹ groups together with the nitrogen atom to which they are        attached optionally form a 5-7-membered heterocycloalkyl, the        heterocycloalkyl optionally comprising one or more further        heteroatom independently selected from —O—, —N(R³)—, —S—, —S(O)—        and —SO₂—.

According to one example, the compound is of Formula I, wherein R⁵, R⁸and R¹⁰ are other than —H.

Herein, the following groups contained in Formula I:

which is an aromatic ring, may be referred to herein as radical “Z”. Aswill be apparent from the above, in Formula II, X², X³, and X⁵, can eachrepresent a covalent bond, with the proviso that at most only one of X²,X³, and X⁵ represents a covalent bond. In other words, the group ofFormula II is a five- or six-membered aromatic ring (the term aromaticincluding also heteroaromatic).

Furthermore, the above general chemical formula comprises the provisothat one of X² and X³ is —C(A)═ and the other of X² and X³ is —CH═ or acovalent bond. This means that when X³ represents a covalent bond, thenX² and X⁵ are not covalent bonds and X² must be —C(R²)═. In other words,when X³ represents a covalent bond, Formula II corresponds to thefollowing Formula III:

wherein X⁵ is —C(R³)═ or —O—. Similarly, when X² represents a covalentbond, X³ and X⁵ are not covalent bonds and X³ must be —C(R²)═, and thusFormula II also corresponds to formula III wherein X⁵ is —C(R³)═ or —O—.Thus, in some examples, one of X² and X³ represents a covalent bond, theother of X² and X³ represents —C(R²)═, and X⁵ represents —C(R³)═, or—O—, while X¹ and X⁴ are as herein defined.

When X⁵ represents a covalent bond, neither X² or X³ can be a covalentbond, which means that one of them is —C(R²)═ and the other is —CH═. Inother words, when X⁵ represents a covalent bond, Formula II correspondsto the following Formulas IV and IV′:

obtained when X² is —C(R²)═ and X³ is —CH═; and

obtained when X² is —CH═ and X³ is —C(R²)═.

Also included are compounds where in Formula II, none of X², X³, and X⁵are covalent bonds. In which case, one of X² and X³ is —C(R²)═ and theother is —CH═, while X⁵ is —C(R³)═ or —O— and X¹ and X⁴ are as definedabove. Preferred such groups of Formula II include:

In some embodiments, X³ is —CH═. In alternative embodiments, X³ is acovalent bond. In yet other embodiments, X³ is —C(R²)═. In some otherembodiments, X² is —CH═. In alternative embodiments, X² is a covalentbond. In yet other embodiments, X² is —C(R²)═. In further embodiments,X¹ is —N═ or —CH═. In other embodiments, X¹ is —N═. In alternativeembodiments, X¹ is —CH═. In other embodiments, X¹ is —O—. Inembodiments, X⁴ is —O—. In alternative embodiments, X⁴ is —C(R³)═, forinstance, wherein R³ is H (i.e. X⁴ being —CH═). In other alternativeembodiments, X⁴ is —N═. In yet other alternative embodiments, X⁴ is —S—.In embodiments, X⁵ is a covalent bond. In alternative embodiments, X⁵ is—C(R³)═, for instance, wherein R³ is H (i.e. X⁵ being —CH═). In otheralternative embodiments, X⁵ is —O—.

In some embodiments, in the group of Formula II, X¹ and X³ each are—CH═, X² is —C(R²)═, and X⁴ and X⁵ each are —C(R³)═, wherein, in furtherembodiments, R³ preferably represents H. In other embodiments, in thegroup of Formula II, X¹ and X³ each represent —CH═, X² represents—C(R²)═, X⁴ is —N═ and X⁵ represents —C(R³)═, wherein, in furtherembodiments, R³ preferably represents H.

In preferred embodiments, in the group of Formula III, one of X² and X³is a covalent bond and the other is —C(R²)═. In preferred suchembodiments, X¹ represents —N═, X⁴ represents —O— or —S—, preferably—O—, and X⁵ represents —C(R³)═, wherein, in further embodiments, R³preferably represents H.

As noted above, R² represents ArylC(R³)═C(H)—, HeteroarylC(R³)═C(H)—,ArylN(R³)C(O)—, HeteroarylN(R³)C(O)—, Arylcyclopropyl-,Heteroarylcyclopropyl-, R³OC(O)C(H)═C(H)—, R³OC(O)—, Aryl-C≡C—,Heteroaryl-C≡C—, Aryl-, Heteroaryl-, Aryl-CH(R³)—CH(R³)—, orHeteroaryl-CH(R³)—CH(R³)—. In preferred embodiments, R² representsArylC(R³)═C(H)—, HeteroarylC(R³)═C(H)—, ArylN(R³)C(O)—,Arylcyclopropyl-, R³OC(O)C(H)═C(H)—, R³OC(O)—, Aryl-, Heteroaryl-, orAryl-CH(R³)—CH(R³)—. In more preferred embodiments, R² representsArylC(R³)═C(H)— or Heteroaryl, and more preferably ArylC(R³)═C(H)—.

In preferred embodiments, the Aryl group in R² is phenyl or naphthyl,more preferably phenyl.

In preferred embodiments, the Heteroaryl group in R² is selected from:

(wherein n represents an integer from 0 to 3, X⁸ represents —NH—, —O—,or —S—, preferably —NH—, and X⁹ is —N═ or —CH═, preferably —CH═),pyridyl, pyrimidinyl, thienyl, isoxazolyl, quinolyl, isoquinolyl,indolyl, indolinyl, benzo[b]thienyl, benzimidazolyl, benzoxalolyl,benzofuranyl, isobenzofuranyl and benzothiazolyl, including any tautomerthereof. Preferably, Heteroaryl groups include

or pyridyl, and more preferably

As noted above, all of these Aryl and Heteroaryl groups are optionallysubstituted with one to three R⁴ groups, which are the same ordifferent.

In R², preferred embodiments of ArylC(R³)═C(H)— include

In R², preferred embodiments of HeteroarylC(R³)═C(H)— include

In R², preferred embodiments of Arylcyclopropyl-include

In R², preferred embodiments of AryIN(R³)C(O)— include

In R², preferred embodiments of R³OC(O)— include MeOC(O)—.

In R², preferred embodiments of Aryl-CH(R³)—CH(R³)— include

In R², preferred embodiments of Aryl include

In R², preferred embodiments of Heteroaryl include

-   -   wherein n represents an integer from 0 to 3, X⁸ represents —NH—,        —O—, or —S—, preferably —NH—, and X⁹ is —N═ or —CH═, preferably        —CH═.

In any and all of the above embodiments of R², R³ preferably representsH or CH₃, more preferably H.

In any and all of the above embodiments of R², n represents an integerfrom 0 to 3 and R⁴ is as defined above. In other words, the Aryl and/orthe Heteroaryl contained in R² are optionally substituted with one tothree (preferably one to two) R⁴ groups, the same or different,preferably different. In other words, n is 0 to 3 in the above formulawhere it is present and preferably n is 0 to 2). In embodiments, thesegroups are unsubstituted (n=0). In alternative embodiments, these groupsare substituted with one to three (i.e., n is 1 to 3), preferably one totwo (n is 1 or 2), R⁴ groups, the same or different, preferablydifferent. In embodiments, these groups are substituted with one R⁴group (n=1). In embodiments, these groups are substituted with two R⁴groups (n=2), the same or different, preferably different. Inembodiments, these groups are substituted with three R⁴ groups (n=3),the same or different, preferably different. The R⁴ groups optionallysubstituting the Aryl and/or the Heteroaryl contained in R² may belocated at any position.

Examples of R² groups comprising 6-membered Aryl and Heteroaryl group inwhich the one R⁴ group is preferably at position 2 include:

-   -   ArylC(R³)═C(H)— is preferably

and

-   -   HeteroarylC(R³)═C(H)— more preferably

Examples of R² groups comprising 6-membered Aryl and Heteroaryl group inwhich the one R⁴ group is preferably at position 3 includeArylC(R³)═C(H)—, preferably

Examples of R² groups comprising 6-membered Aryl and Heteroaryl group inwhich the one R⁴ group is preferably at position 4 include:

-   -   ArylC(R³)═C(H)— preferably

-   -   Arylcyclopropyl-, preferably

and

Aryl-, preferably

Furthermore, when the one R⁴ group substitutes the

group, it is preferably at position 5 or 6, preferably 5. Such a groupwhich is preferably substituted at position 5 or 6 is

wherein X⁸ is preferably —NH—.

Alternatively, when there are two R⁴ groups (same or different),preferably different, substituting a 6-membered Aryl and Heteroaryl,preferably Aryl, preferably phenyl, they are preferably at positions 2and 4, positions 3 and 4, or positions 2 and 6, more preferably atpositions 2 and 4. Examples of R² groups comprising 6-membered Arylgroup in which the two R⁴ groups are thus located includeArylC(R³)═C(H)— and ArylN(R³)C(O)—, preferably ArylC(R³)═C(H)—, whereinAryl is phenyl.

Furthermore, when two R⁴ groups substitutes the

group, they are preferably at positions 5 and 7. A preferred such groupwhich is preferably substituted at positions 5 and 7 is

wherein X⁸ is preferably —NH—.

Alternatively, when there are three R⁴ groups (same or different),preferably the same, substituting a 6-membered Aryl and Heteroaryl,preferably Aryl, preferably phenyl, they are preferably at positions 3,4, and 5. Examples of R² groups comprising 6-membered Aryl group inwhich the three R⁴ group are thus located include ArylC(R³)═C(H)—,wherein Aryl is phenyl.

It will be noted above that the definition of R⁴ refers in manyinstances to R³ groups. Preferred R³ groups (when in R⁴) include —H,—C₁-C₅ alkyl, —C₂-C₅ alkynyl, or —C₁-C₄ fluoroalkyl. In suchembodiments, a preferred C₁-C₅ alkyl is methyl. Furthermore, preferredC₂-C₅ alkynyl groups include —C≡CH and —CH₂—C≡CH. Furthermore, apreferred —C₁-C₄ fluoroalkyl is —CF₃.

In preferred embodiments, R⁴ represents —F, —Cl, —Br, —I,—S(O)₂—C₁-C₅alkyl, -triazolyl, —CN, —C(O)OR³, —NO₂, —C(O)N(R³)₂, —OR³,—C(R³)₂OH, —N(R³)₂, —N₃, —R³,

In more preferred embodiments, R⁴ represents —F, —Br, —Cl, —CF₃,—S(O)₂Me, -triazolyl, —CN, —NO₂, —OCF₃, —OMe, —C(O)OMe, —CH₂OH, —OH,—C(O)NH₂, —NH₂, —N₃, —C(O)NHCH₂C≡CH, —C≡CH,

Most preferred R⁴ groups include —F, —Br, —Cl, —CF₃, —S(O)₂Me, —CN,—NO₂, —OH, —OMe, —OCF₃, —N₃, CH₂OH, or —C(O)OMe.

When there is only one R⁴ group, R⁴ preferably represents F, Cl, Br, CN,CO₂Me, NO₂, OH, OCF₃, CH₂OH, or CF₃, preferably —F, —Cl, —Br, —CN,—CO₂Me, —NO₂, —OCF₃, —CH₂OH, or —CF₃, more preferably —F, —Br, —Cl,—CF₃, CO₂Me, —NO₂, —CN, —OCF₃, and —OMe, yet more preferably —F, —Br,—CF₃, CO₂Me, —NO₂, and —CN, even more preferably —F, CO₂Me, —Br, —NO₂,and —CN, and most preferably F or NO₂.

When there are two R⁴ groups, R⁴ preferably represents, independently iseach occurrence, —F, —Br, —Cl, —CF₃, —S(O)₂Me, —NO₂, —OCF₃, —OMe,—C(O)OMe, —NH₂, —N₃,

or -triazolyl, preferably F, Cl, Br, SO₂Me, CN, CO₂Me, NO₂, OMe, OCF₃,N₃, or CF₃, more preferably F, Cl, Br, CN, CO₂Me, NO₂, OCF₃, or CF₃, yetmore preferably —F, —Br, —Cl, —CF₃, CN, NO₂, OCF₃, or —NO₂, and mostpreferably F, CN, NO₂, OCF₃, or CF₃. Preferred R⁴ pairs include thosewherein one of the two R⁴ groups is F or —CF₃. Preferred R⁴ pairsinclude Cl/Cl, F/N₃, F/Br, F/Cl, F/NH₂, F/CN, F/CF₃, F/S(O)₂Me, F/NO₂,F/OCF₃, F/OMe, F/C(O)OMe, F/F, F/triazolyl, F/N₃,

CF₃/NO₂, or

preferably F/Br, F/Cl F/CN, F/CF₃, F/S(O)₂Me, F/NO₂, F/OCF₃, F/OMe,F/C(O)OMe, F/N₃, F/NO₂ and F/F, more preferably F/F, F/Cl, F/Br, F/CN,F/CO₂Me, F/NO₂, F/OCF₃, or F/CF₃, and most preferably F/CN, F/NO₂,F/OCF₃, or F/CF₃.

When there are three R⁴ groups, all R⁴ preferably represent —F.

Herein, the term “triazolyl” indicate a monovalent radical of triazole,wherein the triazole can be any isomer and tautomer thereof. Triazolesare defined in the art as heterocyclic compounds of molecular formulaC₂H₃N₃, having a five-membered ring of two carbon atoms and threenitrogen atoms. There are two sets of isomers that differ in therelative positions of the three nitrogen atoms. Each of these has twotautomers that differ by which nitrogen has a hydrogen bonded to it.Thus, the term “triazole” encompasses:

Herein, the triazolyl can be attached to the rest of the molecule by anyof their available ring atoms. Preferred triazolyl groups include1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, and 1,2,4-triazol-1-yl. A mostpreferred triazolyl (in R⁴) include 1,2,3-triazol-2-yl.

Preferred

groups include those where R³ is H, p is 2, and/or R⁶ is H.

Preferred embodiments of

thus include

In preferred embodiments of

(as found in R⁴), wherein both X⁶ and X⁷ are —CH═; L² is a covalentbond, m is 1 to 4, preferably 4, and/or R¹ is a heteroaryl, morepreferably a triazolyl group as defined herein. Preferred triazolylgroups include 1,2,4-triazol-1-yl and 1,2,3-triazol-1-yl. Most preferred

groups include:

preferably

In preferred embodiments of Formula I, L¹ represents —CHR³—O—, —CH₂—NH—,—C(O)NH—, —CR⁶═CR⁶—, —CH₂—S—, or —CH₂—, preferably —CHR³—O—, —CH₂—NH—,or —CR⁶═CR⁶—, and most preferably —CHR³—O—. In preferred embodiments, inL¹, R³ is H. In preferred embodiments, in L¹, R⁶ is H.

In preferred embodiments of Formula I, both X⁶ and X⁷ represent —CR³═ orone of X⁶ and X⁷ represents —CR³═ and the other represents —NH═,preferably both X⁶ and X⁷ represent —CR³═. In preferred embodiments, inX⁶ and X⁷, R³ is H.

In preferred embodiments of Formula I, L² represents a covalent bond,—C(O)—, —C(R³)(OH)—, —O—, —S—, or —CHR³—O—, In more preferredembodiments, L² preferably represents a covalent bond, —C(O)—,—C(R³)(OH)—, or —S—, most preferably a covalent bond or —S—. Inpreferred embodiments, in L², R³ is H.

In preferred embodiments, m represents 2, 3 or 4, preferably 3 or 4, andmore preferably 4.

In preferred embodiments of Formula I, R¹ represents heteroaryl, —N₃,—OH, —OC(O)N(R⁷)₂, —C(O)N(R⁷)₂, —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁸, or—N(R⁷)C(O)-L³—OC(O)N(R⁷)₂, preferably heteroaryl, —N(R⁷)C(O)R⁷, or—N(R⁷)C(O)-L³—OC(O)N(R⁷)₂, and more preferably heteroaryl, theheteroaryl being optionally substituted with one or more R⁹, which arethe same or different; R⁷, R⁸, R⁹ and L³ being as defined above.

In preferred embodiments, R⁷ is —H, or -C₁-C₅alkyl, the alkyl beingoptionally substituted with one or more R⁹, which are the same ordifferent, or

-   -   when two R⁷ groups are attached to a same nitrogen atom, the two        R⁷ groups together with the nitrogen atom to which they are        attached optionally form a 5-7-membered heterocycloalkyl, the        heterocycloalkyl comprising one or more further heteroatom or        heteoatom-containing group independently selected from —O—,        —N(R³)—, —S—, —S(O)—, and —SO₂—, the heterocycloalkyl being        optionally substituted with one or more R⁹, which are the same        or different.

In preferred embodiments, the alkyl in R⁷ is methyl, ethyl, or butyl(which is more preferably t-butyl). In preferred embodiments, theheterocycloalkyl optionally formed when two R⁷ groups are attached to asame nitrogen atom, is a 6-membered heterocycloalkyl. In embodiments,the heterocycloalkyl comprises one or more, preferably one, furtherheteroatom. In preferred embodiments, this heteroatom is oxygen. In mostpreferred embodiments, the heterocycloalkyl is 4-morpholinyl. As notedabove, the heterocycloalkyl being optionally substituted with one ormore R⁹, which are the same or different. In preferred embodiments, theheterocycloalkyl is unsubstituted.

As noted above, the alkyl, alkenyl, alkynyl, cycloalkyl, alkylene, andheterocycloalkyl in R⁷ are optionally substituted with one or more R⁹,which are the same or different (and which are as defined above). Inpreferred embodiments, these groups are unsubstituted. In alternativeembodiments, these groups in R¹ are substituted, preferably with one ortwo, more preferably with one R⁹. In such specific embodiments, R⁹, whenit substitutes the alkyl, alkenyl, alkynyl, cycloalkyl, or alkylenegroup, preferably the alkyl, in R⁷ represent —OH.

In preferred embodiments, R⁸ is —H, or -C₁-C₅alkyl, the alkyl beingoptionally substituted with one or more R⁹, which are the same ordifferent. More preferably, the alkyl in R⁸ is methyl, ethyl, or butyl(which is more preferably t-butyl). As noted above, the alkyl, alkenyl,alkynyl, cycloalkyl, alkylene, and heterocycloalkyl in R⁸ are optionallysubstituted with one or more R⁹, which are the same or different (andwhich are as defined above). In preferred embodiments, these groups areunsubstituted. In alternative embodiments, these groups in R¹ aresubstituted, preferably with one or two, more preferably with one R⁹. Insuch specific embodiments, R⁹, when it substitutes the alkyl, alkenyl,alkynyl, cycloalkyl, or alkylene group, preferably the alkyl, in R⁸represent —OH.

In preferred embodiments, L³ represents C₁-C₅ alkylene, preferablyethylene. As noted above, the alkylene, alkenylene, and alkynylene in L³are optionally substituted with one or more R⁹, which are the same ordifferent (and which are as defined above). In preferred embodiments,these groups are unsubstituted.

In preferred embodiments, the heteroaryl in R¹ is triazolyl, imidazolyl,pyrazolyl, pyridinyl, thiazolyl, pyrimidinyl, tetrazolyl, pyrazinyl,pyridazinyl, oxadiazolyl, or thiadiazolyl, preferably triazolyl,imidazolyl, pyridinyl, thiazolyl, pyrimidinyl, pyridazinyl, ortetrazolyl, more preferably triazolyl, pyridazinyl, or imidazolyl, andmost preferably pyridazinyl or triazolyl, each of which being optionallysubstituted with one or more R⁹, which are the same or different.

In embodiments, the triazolyl in R¹ is a 1,2-3-triazolyl or a1,2-4-triazolyl, most preferably 1,2,3-triazol-1-yl or1,2,4-triazol-1-yl-which are as noted above optionally substituted withone or more R⁹, which are the same or different.

Herein, the term “imidazolyl” indicates a monovalent radical ofimidazole and any tautomer thereof. The imidazolyl can be attached tothe rest of the molecule by any of its available ring atoms. In someembodiments, the imidazolyl in R¹ is imidazol-1-yl (i.e., linked by oneof its nitrogen atoms) —which is as noted above optionally substitutedwith one or more R⁹, which are the same or different.

Herein, the term “pyrazolyl” indicates a monovalent radical of pyrazoleand any tautomer thereof. The pyrazolyl can be attached to the rest ofthe molecule by any of its available ring atoms. In embodiments, thepyrazolyl in R¹ is pyrazol-1-yl (i.e., linked by one of its nitrogenatoms)-which is as noted above optionally substituted with one or moreR⁹, which are the same or different.

Herein, the terms “pyridyl” and “pyridinyl”, which are synonymous, bothindicate a monovalent radical of pyridine. The pyridinyl can be attachedto the rest of the molecule by any of its available ring atoms. Inembodiments, the pyridinyl in R¹ is pyridin-3-yl or pyridin-4-yl-whichare as noted above optionally substituted with one or more R⁹, which arethe same or different.

Herein, the term “thiazolyl” indicates a monovalent radical of thiazole.The thiazolyl can be attached to the rest of the molecule by any of itsavailable ring atoms. In embodiments, the thiazolyl in R¹ isthiazol-2-yl-which are as noted above optionally substituted with one ormore R⁹, which are the same or different.

Herein, the terms “pyrimidinyl” indicate a monovalent radical ofpyrimidine. The pyrimidinyl can be attached to the rest of the moleculeby any of its available ring atoms. In embodiments, the pyrimidinyl inR¹ is pyrimidin-5-yl-which is as noted above optionally substituted withone or more R⁹, which are the same or different.

Herein, the term “tetrazolyl” indicates a monovalent radical oftetrazole and any tautomer thereof. The tetrazolyl can be attached tothe rest of the molecule by any of its available ring atoms. In someembodiments, the tetrazolyl in R¹ is 1,2,3,4-tetrazol-1-yl or1,2,3,4-tetrazol-2-yl—which are as noted above optionally substitutedwith one or more R⁹, which are the same or different.

Herein, the term “pyrazinyl” indicates a monovalent radical of pyrazine.The pyrazinyl can be attached to the rest of the molecule by any of itsavailable ring atoms. Herein, the term “pyridazinyl” indicates amonovalent radical of pyridazine.

The pyridazinyl can be attached to the rest of the molecule by any ofits available ring atoms.

Herein, the term “oxadiazolyl” indicates a monovalent radical ofoxadiazole and any tautomer thereof. Oxadizazole is defined in the artas a heterocyclic compound of molecular formula C₂H₂N₂O. There are fourisomers of oxadiazole:

The oxadiazolyl can be attached to the rest of the molecule by any ofits available ring atoms. In some embodiments, the oxadiazolyl in R¹ isa 1,2,4-oxadiazolyl (an example thereof being attached by the carbonbetween the two nitrogen atoms)—which is as noted above optionallysubstituted with one or more R⁹, which are the same or different.

Herein, the term “thiadiazolyl” indicates a monovalent radical ofthiadiazole and any tautomer thereof. Thiadiazole is defined in the artas a heterocyclic compound of molecular formula C₂H₂N₂S. There are fourisomers of thiadiazole:

The thiadiazolyl can be attached to the rest of the molecule by any ofits available ring atoms. In some embodiments, the thiadiazolyl in R¹ isa 1,2,4-thiadiazolyl—which is as noted above optionally substituted withone or more R⁹, which are the same or different.

In more preferred embodiments, the heteroaryl in R¹ is a1,2,3-triazolyl, a 1,2-4-triazolyl, an imidazolyl, a pyrazolyl, apyridinyl, a pyridazinyl, a thiazolyl, a pyrimidinyl, or a1,2,3,4-tetrazolyl, preferably an imidazolyl, a pyridazinyl, or a1,2,3-triazolyl, more preferably a pyridazinyl or 1,2,3-triazolyl.

In yet more preferred embodiments, the heteroaryl in R¹ is1,2,3-triazol-1-yl, 1,2-4-triazolyl, imidazol-1-yl, pyrazol-1-yl,pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, thiazol-2-yl,pyrimidin-5-yl, 1,2,3,4-tetrazol-1-yl, or 1,2,3,4-tetrazol-2-yl,preferably 1,3-imidazol-1-yl, pyridazin-3-yl, or 1,2,3-triazol-1-yl,more preferably pyridazin-3-yl or 1,2,3-triazol-1-yl.

As noted above, the aryl and the heteroaryl in R¹ are optionallysubstituted with one or more R⁹, which are the same or different (andwhich are as defined above). In preferred embodiments, the aryl andheteroaryl in R¹ are unsubstituted. In alternative embodiments, the aryland the heteroaryl in R¹ are substituted, preferably with one or two R⁹,more preferably with one R⁹. In some embodiments, R⁹ (especially whensubstituting the aryl and the heteroaryl in R¹) is —C₁-C₆alkyl,—C₃-C₆alkyl-OR¹¹, —C₃-C₆cycloalkyl-OR¹¹, —C₁-C₅ alkyl-OC(O)N(R¹¹)₂,—C₁-C₅ alkyl- OC(O)N(R¹¹)-L⁴-OR¹¹, —C₀-C₆alkyl-C(O)OR¹¹,—C₀-C₆alkyl-C(O)N(R¹¹)₂, —C₁-C₅ alkyl-N(R¹¹)₂, —C₁-C₅alkyl-N(R¹¹)C(O)R¹¹, —C₁-C₆alkyl-N(R¹¹)S(O)₂R¹⁰, or Si(C₁-C₅alkyl)₃,preferably —C₁-C₅ alkyl-OC(O)N(R¹¹)₂, —C₁-C₆alkyl-OC(O)N(R¹¹)-L⁴—OR¹¹,—C₃- C₆ alkyl-C(O)N(R¹¹)₂, —C₁-C₅ alkyl-N(R¹¹)₂, —C₁-C₅alkyl-N(R¹¹)S(O)₂R¹⁰, or Si(C₁-C₅alkyl)₃, more preferably—C₁-C₆alkyl-OC(O)N(R¹¹)₂, —C₁-C₅ alkyl-OC(O)N(R¹¹)-L⁴—OR¹¹, —C₁-C₅alkyl-N(R¹¹)₂, or Si(C₁-C₅alkyl)₃, and most preferably Si(C₁. C₅alkyl)₃.

In some embodiments, the —C₁-C₆ alkyl moieties in R⁹ are —C₁-C₄,preferably —C₁-C₂, and more preferably —C₂ alkyl moieties; and/or the—C₃-C₆ alkyl moieties are —C₀-C₄, preferably —C₀-C₂, and more preferably—C₀(i.e., the alkyl moiety being absent) or —C₂ alkyl moieties.

As will be noted above, the definitions of R⁹ (general and preferred)refer to groups R¹⁰, R¹¹, and L⁴. In R⁹, the R¹⁰, R¹¹, and L⁴ groups areas defined above.

In more preferred embodiments, R¹¹ is H, —C₁-C₅alkyl, —C₂-C₅alkynyl,—C₁-C₄fluoroalkyl, or —C₃-C₇cycloalkyl or two R¹¹ groups together withthe nitrogen atom to which they are attached optionally form a5-7-membered heterocycloalkyl, the heterocycloalkyl optionallycomprising one or more further heteroatom independently selected from—O—, —N(R³)—, —S—, S(O) and S(O)₂.

In some embodiments, —C₁-C₅alkyl in R¹¹ is methyl, ethyl, propyl(preferably isopropyl), butyl (preferably tert-butyl) or pentyl. Inother embodiments, the —C₂-C₅ alkynyl in R¹¹ is —CH₂CH₂—C≡CH or—CH₂C≡CH. In embodiments, the —C₁-C₄ fluoroalkyl in R¹¹ is —CF₃. Inembodiments, the C₃-C₇ cycloalkyl in R¹¹ is cyclopentyl. In furtherembodiments, the alkyl and alkynyl groups in R¹¹ are unsubstituted.

In embodiments, the heterocycloalkyloptionally formed when two R¹¹groups are attached to a same nitrogen atom is a 6-memberedheterocycloalkyl. In embodiments, the heterocycloalkyl comprising one ormore, preferably one, further heteroatom. Preferably, this heteroatom is—SO₂. In most preferred embodiments, the heterocycloalkyl is

In other preferred embodiments, R¹⁰ is —C₁-C₅alkyl, —C₂-C₅alkynyl,—C₁-C₄fluoroalkyl, or —C₃-C₇cycloalkyl. In some embodiments, —C₁-C₅alkylin R¹⁰ is methyl, ethyl, propyl (preferably isopropyl), butyl(preferably tert-butyl) or pentyl. In other embodiments, the —C₂-C₅alkynyl in R¹⁰ is —CH₂CH₂—C≡CH or —CH₂C≡CH. In embodiments, the —C₁-C₄fluoroalkyl in R¹⁰ is —CF₃. In embodiments, the C₃-C₇ cycloalkyl in R¹⁰is cyclopentyl. In further embodiments, the alkyl and alkynyl groups inR¹⁰ are unsubstituted.

In other embodiments, L⁴ represents C₁-C₅ alkylene, preferably ethylene.

In embodiments, in C₁-C₆alkyl-OR¹¹ in R⁹, R¹¹ represents H. Inembodiments, in —C₃-C₆cycloalkyl-OR¹¹ in R⁹, R¹¹ represents H. Inembodiments, in —C₁-C₅ alkyl-OC(O)N(R¹¹)₂ in R⁹, both R¹¹ groupsrepresent methyl or one R¹¹ group represents H and the other representspropyl (preferably isopropyl), butyl (preferably tertbutyl), orcyclopentyl. In embodiments, in —C₁-C₅ alkyl-OC(O)N(R¹¹)-L⁴—OR¹¹ in R⁹,N(R¹¹) represents NH, L⁴ represents ethylene and/or OR¹¹ represents OH.In embodiments, in —C₀-C₆alkyl-C(O)OR¹¹ in R⁹, R¹¹ represents ethyl ortert-butyl. In embodiments, in —C₀-C₆alkyl-C(O)N(R¹¹)₂ in R⁹, one R¹¹represents H and the other represents an alkynyl, preferably —CH₂—C≡CH.In embodiments, in —C₁-C₅ alkyl-N(R¹¹)₂ in R⁹, both R¹¹ groups representH, or one R¹¹ group represents H and the other represents methyl, orboth R¹¹ together with the nitrogen atom to which they are attached form

In embodiments, in —C₁-C₆alkyl-N(R¹¹)C(O)R¹¹ in R⁹, N(R¹¹) represents NHand/or C(O)R¹¹ represents an C(O)-alkyne, preferably C(O)—CH₂CH₂—C≡CH.In embodiments, in —C₁-C₅ alkyl-N(R¹¹)S(O)₂R¹⁰ in R⁹, N(R¹¹) representsNH and/or S(O)₂R¹⁰ represents S(O)₂Me or S(O)₂CF₃.

In most preferred embodiments, R⁹ (especially when substituting the arylor the heteroaryl in R¹) represents Me, —SiMe₃, —CH₂OH, —(CH₂)₂OH,—(CH₂)₃OH, —(CH₂)₄OH, —CH₂NH₂, —(CH₂)₂NH₂, —CH₂NHMe, —C(O)OEt,

—(CH₂)₂O—C(O)NMe₂, —(CH₂)₂NH—SO₂—Me, —(CH₂)₂NH—SO₂—CF₃,—(CH₂)₂O—C(O)NH—(CH₂)₂OMe, —(CH₂)₂O—C(O)NH—isopropyl,—(CH₂)₂O—C(O)NH-cyclopentyl,

—(CH₂)₄—C(O)—NH—CH₂—C≡CH, —(CH₂)₂NHC(O)(CH₂)₂—C≡CH, or

In preferred embodiments, the heteroaryl in R¹ is:

preferably

and more preferably

wherein R¹³, R¹⁴ and R¹⁵ are independently H or R⁹, wherein R⁹ is asdefined herein (including the general definition and the preferredembodiments thereof).

Overall, in more preferred embodiments, R¹ represents —N₃,—C(O)—N(H)—CH₂—C≡CH, —OH, —OC(O)—(N-morpholine), —O—C(O)—NMe₂,—O—C(O)—NEt₂, —N(H)C(O)H, —N(H)—C(O)O-tert-butyl; —N(H)—C(O)—(CH₂)₂OH,—N(H)—C(O)— (CH₂)₂OC(O)NMe₂,

preferably

and more preferably

wherein R¹³, R¹⁴ and R¹⁵ are independently H or R⁹, wherein R⁹ is asdefined herein (including the general definition and the preferredembodiments thereof).

In preferred embodiments, R¹³ represents H, Me, SiMe₃, —CH₂OH,—(CH₂)₂OH, —(CH₂)₃OH, —(CH₂)₄OH, —C(O)OEt, —CH₂NHMe,

—CH₂NH₂, —(CH₂)₂NH₂, —(CH₂)₄—C(O)—NH—C≡CH, —(CH₂)₂NHC(O)(CH₂)₂—C≡CH,—(CH₂)₂OCONMe₂, —(CH₂)₂O—C(O)NH—(CH₂)₂OMe, —(CH₂)₂O—C(O)NH-isopropyl,—(CH₂)₂O—C(O)NH-tertbutyl, or —(CH₂)₂O—C(O)NH-cyclopentyl, preferably H,—(CH₂)₂NHC(O)(CH₂)₂—C≡CH, —(CH₂)₂OCONMe₂, —(CH₂)₂O—C(O)NH—isopropyl,—(CH₂)₂O—C(O)NH-cyclopentyl, —(CH₂)₂O—C(O)NH—(CH₂)₂OMe,

or —SiMe₃, more preferably H or —SiMe₃, and most preferably H.

In preferred embodiments, R¹⁴ represents H, —C(O)OEt, —CH₂OH, —(CH₂)₂OH,or

preferably H.

In preferred embodiments, R¹⁵ represents H, —(CH₂)₂OH, —(CH₂)₂NH₂,—(CH₂)₂OC(O)—NMe₂, —(CH₂)₂NH—SO₂Me, or —(CH₂)₂NH—SO₂CF₃, preferably H,—(CH₂)₂OCONMe₂, —(CH₂)₂NH—SO₂Me, or —(CH₂)₂NH—SO₂CF₃, more preferably Hor —(CH₂)₂OCONMe₂, and most preferably H.

In more preferred embodiments, especially when R¹ is

-   -   both R¹³ and R¹⁴ are H;    -   R¹³ is R⁹, wherein R⁹ is as defined in any one of claims above,        and R¹⁴ is H;    -   both R¹³ and R¹⁴ are —C(O)OEt;    -   both R¹³ and R¹⁴ are —CH₂OH; or    -   R¹³ is H and R¹⁴ is

-   -   most preferably both R¹³ and R¹⁴ are H.

In other preferred embodiments, especially when R¹ is

both R¹³ and R¹⁴ are H, and R¹⁵ is H, —(CH₂)₂OH, —(CH₂)₂NH₂,—(CH₂)₂OC(O)—NMe₂, —(CH₂)₂NH—SO₂Me, or —(CH₂)₂NH—SO₂CF₃, preferably H.

In other preferred embodiments, especially when R¹ is

R¹³ is H.

In other preferred embodiments, especially when R¹ is

R¹³, is R¹⁴, and R¹⁵ are each H.

In other preferred embodiments, especially when R¹ is

R¹³ is H or methyl.

In other preferred embodiments, especially when R¹ is

R¹³ is H or methyl and R¹⁴ is H.

In other preferred embodiments, especially when R¹ is

R¹³ and R¹⁴ are each H.

In other preferred embodiments, especially when R¹ is

R¹³, R¹⁴, and R¹⁵ are each H.

In some embodiments of the compounds of Formula I:

-   -   X¹ is —N═, X² is a covalent bond, X³ is —C(R²)═, X⁴ is —O— or        —S—, and X⁵ is —C(R³)═, wherein        -   R² represents ArylC(R³)═C(H)—, HeteroarylC(R³)═C(H)—,            Heteroaryl-, or

wherein:

-   -   -   the Aryl group and the Heteroaryl group are optionally            substituted with one to three R⁴ groups, which are the same            or different;        -   n represents an integer from 0 to 3;        -   X⁸ represents —NH—, or —O—; and        -   X⁹ is —CH═;        -   R³ independently represents —H, —C₁-C₅alkyl,            —C₁-C₄fluoroalkyl, or —C₃-C₇cycloalkyl, the alkyl being            optionally substituted with —OR⁶;        -   R⁴ independently represents —F, —Cl, —Br, —I, —S(O)₂R⁵, —CN,            —C(O)OR³, —NO₂, —OR³, —C(R³)₂OH, —N₃, or —R³;        -   R⁵ independently represents —C₁-C₅alkyl, —C₁-C₄fluoroalkyl,            or —C₃-C₇cycloalkyl, the alkyl being optionally substituted            with —OR⁶;        -   R⁶ is —H;

    -   L¹ represents —CHR³—O—, —CH₂—NH—, —CH═CH— or —CH₂—O—CH₂—;

    -   L² represents a covalent bond, —C(O)—, —CH(OH)—, or —S—;

    -   X⁶ and X⁷ independently represent —CH═ or —N═;

    -   m is an integer from 1 to 4; and

    -   R¹ represents heteroaryl or —N(R⁷)C(O)R⁷, the heteroaryl being        optionally substituted with one or more R⁹, which are the same        or different, wherein:        -   R⁷ independently represents —C₁-C₅alkyl;        -   R⁹ independently represents —C₁-C₆alkyl, —C₃-C₆alkyl-OR¹¹,            —C₁-C₆alkyl-OC(O)N(R¹¹)₂, —C₃-C₆alkyl-C(O)N(R¹¹)₂,            —C₁-C₆alkyl-N(R¹¹)S(O)₂R¹⁰, or —Si(C₁-C₅alkyl)₃;        -   R¹⁰ independently represents —C₁-C₅alkyl, —C₂-C₅alkynyl, or            —C₃-C₇cycloalkyl, the alkyl, alkynyl, and cycloalkyl being            optionally substituted with —OR⁶;        -   R¹¹ independently represents —C₁-C₅alkyl, —C₂-C₅alkynyl, or            —C₃-C₇cycloalkyl, the alkyl, alkynyl, and cycloalkyl being            optionally substituted with —OR⁶, or        -   when two R¹¹ groups are attached to a same nitrogen atom,            then the two R¹¹ groups together with the nitrogen atom to            which they are attached optionally form a 5 to 7-membered            heterocycloalkyl, the heterocycloalkyl optionally comprising            one or more further heteroatom independently selected from            —O—, —N(R³)—, —S—, —S(O)— and —SO₂—.

In additional embodiments:

represent

wherein R² represents:

and R¹ represents:

OH, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁸, —N(R⁷)C(O)-L³—OR⁷, or—N(R⁷)C(O)-L³—OC(O)N(R⁷)₂, wherein R¹³, R¹⁴ and R¹⁵ are independently Hor R⁹.

In preferred embodiments:

represents

in which X¹ is —N═, X⁴ is —O— or —S—, and X⁵ is —CH═;

-   -   wherein R² represents:

wherein R³ is H or —C₁-C₃alkyl, and either n is 0, or n is 1 to 3 and R⁴independently in each occurrence represents:

-   -   F, Cl, Br, I, —SR³, —SOR⁵, —S(O)₂R⁵, —S(O)₂N(R³)₂, CN, —C(O)OR³,        NO₂, —C(O)NH₂, —OR³, —C(R³)₂OH, —C(O)NH—CH₂—C≡CH, OH, OMe, OCF₃,        CH₂OH, —N(R³)₂, N₃, and —R³;

wherein X⁶ and X⁷ each represent —CH═, L² is a covalent bond, m is 4,and R¹ is

wherein R¹³ and R¹⁴ are each H; or

wherein R³ is H, p is 2 and R⁶ is H;

-   -   L¹ represents —CH₂—O—, —CH₂—NH—, —C(O)NH—, —CH═CH—, —CH₂—S—, or        —CH₂—;    -   L² represents a covalent bond, —C(O)—, —CH(OH)—, —S—, or        —CH₂—O—; X⁶ and X⁷ each represent —CH═ or one of X⁶ and X⁷        represents —CH═ and the other represents —N═; m is an integer        from 1 to 4; and    -   R¹ represents

OH, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁸, —N(R⁷)C(O)-L³—OR⁷, or—N(R⁷)C(O)-L³—OC(O)N(R⁷)₂, wherein:

-   -   -   R¹³, R¹⁴ and R¹⁵ are independently H, methyl,            —C₀-C₆alkyl-OR¹¹, —C₃-C₆cycloalkyl-OR¹¹,            —C₃-C₆alkyl-C(O)OR¹¹, —C₁-C₅ alkyl-OC(O)N(R¹¹)₂, —C₁-C₅            alkyl-OC(O)N(R¹¹)-L⁴—OR¹¹, —C₀-C₆alkyl-C(O)N(R¹¹)₂, —C₁-C₅            alkyl-N(R¹¹)₂, —C₁-C₅ alkyl-N(R¹¹)C(O)R¹¹, —C₁-C₅            alkyl-N(R¹¹)S(O)₂R¹⁰, —SiMe₃, or

wherein R³ is —H, —C₁-C₅ alkyl, or —C₁-C₄ fluoroalkyl, p is an

-   -   -   integer from 1 to 6;        -   L³ represents C₁-C₅alkylene;        -   R⁷ independently represents —H or —C₁-C₅ alkyl, or the two            R⁷ groups together with the nitrogen atom to which they are            attached optionally form a heterocycloalkyl which is

-   -   -   R⁸ represents —C₁-C₅ alkyl;        -   L⁴ represents C₁-C₅ alkylene;        -   R¹⁰ represents —C₁-C₅ alkyl-C₂-C₅ alkynyl, or —C₃-C₇            cycloalkyl; and        -   R¹¹ is —H, —C₁-C₅ alkyl, —C₂-C₅ alkynyl, or —C₃-C₇            cycloalkyl, or two R¹¹ groups together with the nitrogen            atom to which they are attached optionally form a            5-7-membered heterocycloalkyl which is

In more preferred embodiments:

represents

in which X¹ is —N═, X⁴ is —O— or —S—, and X⁵ is —CH═;

-   -   wherein R² represents:

wherein R³ is H or methyl, X⁸ is —NH—, —O—, or —S—, and either n is 0,or n is 1 to 3 and R⁴ independently in each occurrence represents:

-   -   -   F, Cl, Br, —S(O)₂Me, CN, —CO₂Me, NO₂, —C(O)NH₂,            —C(O)NH—CH₂—C≡CH, —OH, —OMe, —OCF₃, —CH₂OH, —NH₂, N₃, CF₃,            —C≡CH;

wherein X⁶ and X⁷ each represent —CH═, L² is a covalent bond, m is 4,and R¹ is

wherein R¹³ and R¹⁴ are each H; or

wherein R³ is H, p is 2 and R⁶ is H;

-   -   L¹ represents —CH₂—O—, —CH₂—NH—, —C(O)NH—, —CH═CH—, —CH₂—S—, or        —CH₂—; X⁶ and X⁷ each represent —CH═ or one of X⁶ and X⁷        represents —CH═ and the other is —N═;    -   L² represents a covalent bond and m is 3 or 4, or L² represents        —C(O)—, —CH(OH)—, or —S— and m is 3, or L² represents —CH₂—O—        and m is 2; and    -   R¹ represents

wherein R¹⁴ is H and R¹³ is selected from

-   -   -   H, methyl,        -   —C₀-C₆alkyl-OR¹¹, wherein the C₀-C₆alkyl is ethyl or butyl            and R¹¹ is H,        -   —C₃-C₆cycloalkyl-OR¹¹, wherein the C₃-C₆ cycloalkyl is            cyclopentyl and R¹¹ is H,        -   —C₀-C₆alkyl-C(O)OR¹¹, wherein C₃-C₆ alkyl is C₀alkyl (i.e.,            absent) and R¹¹ is ethyl,        -   —C₁-C₆alkyl-OC(O)N(R¹¹)₂, wherein the C₁-C₆alkyl is ethyl            and either both R¹¹ groups are methyl, or one R¹¹ group is            isopropyl or cyclopentyl and the other R¹¹ group is H,        -   —C₁-C₆alkyl-OC(O)N(R¹¹)-L⁴—OR¹¹, wherein the C₁-C₆alkyl is            ethyl, N(R¹¹) is NH, L⁴ is ethyl, and —OR¹¹ is —OMe,        -   —C₀-C₆alkyl-C(O)N(R¹¹)₂, wherein C₀-C₆alkyl is butyl and one            R¹¹ group is —CH₂—C≡CH, and the other R¹¹ group is H,        -   C₁-C₆alkyl-N(R¹¹)₂, wherein the C₁-C₆alkyl is methyl and            both R¹¹ are H, or one R¹¹ is H and the other R¹¹ is methyl,            or the two R¹¹ groups taken together with the nitrogen atom            to which they are attached form a 5-7-membered            heterocycloalkyl which is

-   -   -   C₁-C₅ alkyl-N(R¹¹)C(O)R¹¹, wherein the C₁-C₅ alkyl is ethyl,            N(R¹¹) is NH, and C(O)R¹¹ is C(O)—CH₂—C≡CH,        -   —SiMe₃, and

wherein R³ is —H and p is 2;

-   -   -   or both R¹³ and R¹⁴ are CO₂Et or CH₂OH;        -   or R¹³ is H and R¹⁴ is C₁-C₆alkyl-N(R¹¹)₂ wherein the C₁-C₅            alkyl is methyl and the two R¹¹ groups taken together with            the nitrogen atom to which they are attached form a            5-7-membered heterocycloalkyl which is

wherein R¹³ and R¹⁴ are H and R¹⁵ is selected from:

-   -   -   H,        -   —C₀-C₆alkyl-OR¹¹ wherein the C₀-C₆alkyl is ethyl and R¹¹ is            H,        -   —C₁-C₆alkyl-OC(O)N(R¹¹)₂ wherein the C₁-C₅ alkyl is ethyl            and both R¹¹ groups are methyl,        -   —C₁-C₆alkyl-N(R¹¹)₂ wherein the C₁-C₅ alkyl is ethyl and            both R¹¹ groups are H, and        -   —C₁-C₆alkyl-N(R¹¹)S(O)₂R¹⁰, wherein the C₁-C₅ alkyl is            ethyl, R¹¹ is H, and R¹⁰ is Me or SO₂CF₃;

wherein R¹³, R¹⁴, and R¹⁵ are each H;

wherein R¹³ is H or methyl and R¹⁴ is H;

wherein R¹³ is H or methyl;

wherein R¹³ is H;

-   -   OH;    -   —OC(O)N(R⁷)₂, wherein both R⁷ are methyl or ethyl or the two R⁷        groups taken together with the nitrogen atom to which they are        attached form a heterocycloalkyl which is

-   -   —N(R⁷)C(O)R⁷, wherein R⁷ is H in each occurrence;    -   —N(R⁷)C(O)OR⁸, wherein R⁷ is H and R⁸ is tert-butyl;    -   —N(R⁷)C(O)-L³—OR⁷, wherein N(R⁷) is NH, L³ is ethylene, and OR⁷        is OH; or    -   —N(R⁷)C(O)-L³—OC(O)N(R⁷)₂, wherein —N(R⁷)C(O)— is —NHC(O)—, L³        is ethylene, and N(R⁷)₂ is NH₂.

In yet more preferred embodiments:

represents

in which X¹ is —N═, X⁴ is —O— or —S—, and X⁵ is —CH═;

-   -   wherein R² represents:

wherein R³ is H and

-   -   -   n is 0;        -   n is 3 and R⁴ is located on positions 3, 4, and 5 and is F            in each occurrence;        -   n is 2 and R⁴ is located on positions 2 and 4 and is            independently in each occurrence selected from F, Cl, Br,            SO₂Me, CN, CO₂Me, NO₂, OMe, OCF₃, N₃, and CF₃;        -   n is 2 and R⁴ is located on positions 3 and 4 and is F in            each occurrence; or        -   n is 1 and R⁴ is located on position 2 or 4 and is selected            from F, Cl, Br, CN, CO₂Me, NO₂, OH, OCF₃, CH₂OH, and CF₃;

wherein R³ is H and either n is 0, or n is 1 and R⁴ is located atposition 2 and is F, or

wherein X⁸ is —NH—, —O—, or —S—, and

-   -   -   n is 0;        -   n is 2 and R⁴ is located at positions 5 and 7 and is F in            each occurrence; or        -   n is 1 and R⁴ is located at position 5 or 6 and is F or NO₂;

    -   L¹ represents —CH₂—O—, —CH₂—O—CH₂—, —CH₂—NH—, or —CH═CH—;

    -   X⁶ and X⁷ each represent —CH═ or one of X⁶ and X⁷ represents        —CH═ and the other is —N═;

    -   L² represents a covalent bond and m is 4, or L² represents        —C(O)—, —CH(OH)—, or —S— and m is 3, or L² represents —CH₂—O—        and m is 2; and

    -   R¹ represents

wherein R¹⁴ is H and R¹³ is selected from:

-   -   -   H, methyl,        -   —C₁-C₆alkyl-OC(O)N(R¹¹)₂, wherein the C₁-C₆alkyl is ethyl            and either both R¹¹ groups are methyl, or one R¹¹ group is            isopropyl or cyclopentyl and the other R¹¹ group is H,        -   —C₁-C₆alkyl-OC(O)N(R¹¹)-L⁴—OR¹¹, wherein the C₁-C₆alkyl is            ethyl, N(R¹¹) is NH, L⁴ is ethyl, and —OR¹¹ is —OMe,        -   —C₀-C₆alkyl-C(O)N(R¹¹)₂, wherein C₀-C₆alkyl is butyl and one            R¹¹ group is —CH₂—C≡CH, and the other R¹¹ group is H,        -   —C₁-C₆alkyl-N(R¹¹)₂, wherein the C₁-C₅ alkyl is methyl and            the two R¹¹ groups taken together with the nitrogen atom to            which they are attached form a heterocycloalkyl which is

and

-   -   -   —SiMe₃;

wherein R¹³ and R¹⁴ are H and R¹⁵ is selected from:

-   -   -   H,        -   —C₁-C₅ alkyl-OC(O)N(R¹¹)₂ wherein the C₁-C₅ alkyl is ethyl            and both R¹¹ groups are methyl, and        -   —C₁-C₆alkyl-N(R¹¹)S(O)₂R¹⁰, wherein the C₁-C₅ alkyl is            ethyl, R¹¹ is H, and R¹⁰ is Me or CF₃;

-   -   wherein R¹³ is H; or    -   —N(R⁷)C(O)-L³—OC(O)N(R⁷)₂, wherein —N(R⁷)C(O)— is —NHC(O)—, L³        is ethylene, and N(R⁷)₂ is NH₂.

In other preferred embodiments:

represents

in which X¹ is —N═, X⁴ is —O— or —S—, and X⁵ is —CH═;

-   -   wherein R² represents:

wherein R³ is H and

-   -   -   n is 0;        -   n is 3 and R⁴ is located at positions 3, 4, and 5 and is F            in each occurrence;        -   n is 2 and R⁴ is located at positions 2 and 4 and is:            -   F at position 2 and F, Cl, Br, SO₂Me, CN, CO₂Me, NO₂,                OMe, OCF₃, N₃, or CF₃ at position 4;            -   Cl at position 2 and F at position 4; or            -   Cl at positions 2 and 4;        -   n is 2 and R⁴ is located on positions 3 and 4 and is F in            each occurrence; or        -   n is 1 and R⁴ is located on position 2 or 4 and is selected            from F, Cl, Br, CN, CO₂Me, NO₂, OH, OCF₃, CH₂OH, and CF₃;

wherein R³ is H and either n is 0, or n is 1 and R⁴ is located atposition 2 and is F, or

wherein X⁸ is —NH—, —O—, or —S—, and

-   -   -   n is 2 and R⁴ is located at positions 5 and 7 and is F in            each occurrence; or        -   n is 1 and R⁴ is located at position 5 or 6 and is F or NO₂;

    -   L¹ represents —CH₂—O—, —CH₂—NH—, or —CH═CH—;

    -   X⁶ and X⁷ each represent —CH═;

    -   L² represents a covalent bond and m is 4, or L² represents        —C(O)—, —CH(OH)—, or —S— and m is 3; and

    -   R¹ represents

wherein R¹⁴ is H and R¹³ is selected from

-   -   -   H, methyl,        -   —C₁-C₅ alkyl-OC(O)N(R¹¹)₂, wherein the C₁-C₅ alkyl is ethyl            and either both R¹¹ groups are methyl, or one R¹¹ group is            isopropyl or cyclopentyl and the other R¹¹ group is H,        -   —C₁-C₅ alkyl-OC(O)N(R¹¹)-L⁴—OR¹¹, wherein the C₁-C₅ alkyl is            ethyl, N(R¹¹) is NH, L⁴ is ethyl, and —OR¹¹ is —OMe,        -   C₁-C₅ alkyl-N(R¹¹)₂, wherein the C₁-C₅ alkyl is methyl and            the two R¹¹ groups taken together with the nitrogen atom to            which they are attached form a heterocycloalkyl which is

and

-   -   -   —SiMe₃;

R wherein R¹³ and R¹⁴ are H and R¹⁵ is H or —C₁-C₅ alkyl-OC(O)N(R¹¹)₂wherein the C₁-C₆alkyl is ethyl and both R¹¹ groups are methyl;

wherein R¹³ is H; or

-   -   —N(R⁷)C(O)-L³—OC(O)N(R⁷)₂, wherein —N(R⁷)C(O)— is —NHC(O)—, L³        is ethylene, and N(R⁷)₂ is NH₂.

In yet other preferred embodiments:

represents

in which X¹ is —N═, X⁴ is —O—, and X⁵ is —CH═;

-   -   wherein R² represents:

wherein R³ is H and

-   -   -   n is 2 and R⁴ is located at positions 2 and 4 and is F in            position 2 and F, Cl, Br, SO₂Me, CN, CO₂Me, NO₂, OCF₃, or            CF₃ in position 4;        -   n is 2 and R⁴ is located at positions 3 and 4 and is F in            each occurrence; or        -   n is 1 and R⁴ is located at position 4 and is CN or CO₂Me;            or

wherein X⁸ is —NH— or —O—, and

-   -   -   n is 2 and R⁴ is located at positions 5 and 7 and is F in            each occurrence; or        -   n is 1 and R⁴ is located at position 5 or 6 and is F or NO₂;

    -   L¹ represents —CH₂—O—;

    -   X⁶ and X⁷ each represent —CH═;

    -   L² represents a covalent bond and m is 4, or L² represents        —C(O)—, —CH(OH)—, or —S— and m is 3; and

    -   R¹ represents:

wherein R¹⁴ is H and R¹³ is H or —SiMe₃; or

wherein R¹³, R¹⁴ and R¹⁵ are each H.

In yet other preferred embodiments:

represents

in which X¹ is —N═, X⁴ is —O—, and X⁵ is —CH═; wherein R² represents:

wherein R³ is H, n is 2 and R⁴ is located at positions 2 and 4, and is Fin position 2 and F, Cl, Br, SO₂Me, CN, CO₂Me, NO₂, OCF₃, or CF₃ inposition 4; or

wherein X⁸ is —NH—, and

-   -   -   n is 2 and R⁴ is located at positions 5 and 7 and is F in            each occurrence; or        -   n is 1 and R⁴ is located at position 5 or 6 and is F or NO₂;

    -   L¹ represents —CH₂—O—;

    -   X⁶ and X⁷ each represent —CH═;

    -   L² represents a covalent bond and m is 4, or L² represents —S—        and m is 3; and

    -   R¹ represents

wherein R¹³ and R¹⁴ are each H.

In embodiments, the compound is one of the following (in which thecompound numbers correspond to those used in Example 6) or apharmaceutically acceptable salt thereof:

-   -   Compound 1:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl-2-(4-trifluoromethyl)styryl)oxazole;    -   Compound 2:        (E)-4-((4-(1H-1,2,3-triazol-1-yl-)butyl)phenoxy)methyl)-2-(4-trifluoromethoxy)styryl)oxazole;    -   Compound 3A:        (E)-2-(4-Bromo-2-fluorostyryl)-4-((4-(4-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazole;    -   Compound 3B:        (E)-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-bromo-2-fluorostyryl)oxazole;    -   Compound 4:        (E)-2-(1-(4-(4-((2-(4-Trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl-1H-1,2,3-triazol-4-yl)ethanol;    -   Compound 5:        (E)-4-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl-methoxy)phenyl)butyl-1H-1,2,3-triazol-4-yl)butan-1-ol;    -   Compound 6: (E)-diethyl        1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazole-4,5-dicarboxylate;    -   Compound 7:        (E)-N-methyl-1-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)methanamine;    -   Compound 8:        (E)-1-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)cyclopentanol;    -   Compound 9:        (E)-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazole-4,5-diyl)dimethanol;    -   Compound 10:        (E)-4-((1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)methyl)thiomorpholine        1,1-dioxide;    -   Compound 11:        4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)phenethyl)oxazole;    -   Compound 12:        (E)-N-(prop-2-yn-1-yl)-5-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)pentanamide;    -   Compound 13:        (E)-2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethanamine;    -   Compound 14:        (E)-N-(2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethyl)pent-4-ynamide;    -   Compound 15:        (E)-4-((1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-5-yl)methyl)thiomorpholine        1,1-dioxide;    -   Compound 16:        (E)-4-(1H-1,2,3-triazol-1-yl)-1-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butan-1-one;    -   Compound 17:        (E)-4-(1H-1,2,3-triazol-1-yl)-1-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butan-1-ol;    -   Compound 18:        (E)-4-(1H-1,2,3-triazol-1-yl)-1-(4-((2-(4-(trifluoromethoxy)styryl)oxazol-4-yl)methoxy)phenyl)butan-1-one;    -   Compound 19:        (E)-4-(1H-1,2,3-triazol-1-yl)-1-(4-((2-(4-(trifluoromethoxy)styryl)oxazol-4-yl)methoxy)phenyl)butan-1-ol;    -   Compound 20:        (E)-1-(4-((2-(4-bromo-2-fluorostyryl)oxazol-4-yl)methoxy)phenyl)-4-(1H-1,2,3-triazol-1-yl)butan-1-one;    -   Compound 21:        (E)-1-(4-((2-(4-bromo-2-fluorostyryl)oxazol-4-yl)methoxy)phenyl)-4-(1H-1,2,3-triazol-1-yl)butan-1-ol;    -   Compound 22:        (E)-1-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)-4-(1H-1,2,3-triazol-1-yl)butan-1-one;    -   Compound 23:        (E)-1-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)-4-(1H-1,2,3-triazol-1-yl)butan-1-ol;    -   Compound 24:        (E)-1-(4-((2-(2-fluoro-4-nitrostyryl)oxazol-4-yl)methoxy)phenyl)-4-(1H-1,2,3-triazol-1-yl)butan-1-one;    -   Compound 25:        (E)-1-(4-((2-(2-fluoro-4-nitrostyryl)oxazol-4-yl)methoxy)phenyl)-4-(1H-1,2,3-triazol-1-yl)butan-1-ol;    -   Compound 26:        (E)-4-(4-(1H-1,2,3-triazol-1-yl)butyl)-N-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methyl)aniline;    -   Compound 27:        (E)-4-(4-(1H-1,2,3-triazol-1-yl)butyl)-N-((2-(4-bromo-2-fluorostyryl)oxazol-4-yl)methyl)aniline;    -   Compound 28:        4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-(trifluoromethyl)phenyl)oxazole;    -   Compound 29:        (E)-N-(4-(4-hydroxybutyl)phenyl)-2-(4-(trifluoromethyl)styryl)oxazole-4-carboxamide;    -   Compound 30:        (E)-N-(4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenyl)-2-(4-(trifluoromethyl)styryl)oxazole-4-carboxamide;    -   Compound 31:        (E)-5-(dimethylamino)-N-(2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethyl)naphthalene-1-sulfonamide;    -   Compound 32:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-methoxystyryl)oxazole;    -   Compound 33:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-bromostyryl)oxazole;    -   Compound 34:        (E)-4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl        diethylcarbamate;    -   Compound 35:        (E)-4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl        morpholine-4-carboxylate;    -   Compound 36:        (E)-4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl        dimethylcarbamate;    -   Compound 37:        (E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)benzonitrile;    -   Compound 38:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-chlorostyryl)oxazole;    -   Compound 39:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-fluorostyryl)oxazole;    -   Compound 40:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-nitrostyryl)oxazole;    -   Compound 41:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluorostyryl)oxazole;    -   Compound 42:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-nitrostyryl)oxazole;    -   Compound 43:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(3-nitrostyryl)oxazole;    -   Compound 44:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(trifluoromethyl)styryl)oxazole;    -   Compound 45:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2,4-difluorostyryl)oxazole;    -   Compound 46:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2,6-difluorostyryl)oxazole;    -   Compound 47:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-styryloxazole;    -   Compound 48:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole;    -   Compound 49:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(3-(trifluoromethyl)styryl)oxazole;    -   Compound 50:        (E)-4-((4-(3-(1H-1,2,3-triazol-1-yl)propyl)phenoxy)methyl)-2-(4-(trifluoromethyl)styryl)oxazole;    -   Compound 51:        (E)-2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-imidazol-2-yl)ethanol;    -   Compound 52:        (E)-2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-imidazol-2-yl)ethanamine;    -   Compound 53:        (E)-2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-imidazol-2-yl)ethyl        dimethylcarbamate;    -   Compound 54:        (E)-N-(2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-imidazol-2-yl)ethyl)methanesulfonamide;    -   Compound 55:        (E)-1,1,1-trifluoro-N-(2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-imidazol-2-yl)ethyl)methanesulfonamide;    -   Compound 56:        (E)-1-(4-(4-((3-(4-(trifluoromethyl)styryl)benzyl)oxy)phenyl)butyl)-1H-1,2,3-triazole;    -   Compound 57:        (E)-1-(4-(4-((4-(4-(trifluoromethyl)styryl)benzyl)oxy)phenyl)butyl)-1H-1,2,3-triazole;    -   Compound 58: (E)-methyl        4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)benzoate;    -   Compound 59:        (E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)—N-(prop-2-yn-1-yl)benzamide;    -   Compound 60:        (E)-(4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)phenyl)methanol;    -   Compound 61:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-methoxystyryl)oxazole;    -   Compound 62:        (E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)phenol;    -   Compound 63:        (E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)benzamide;    -   Compound 64:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-ethynylstyryl)oxazole;    -   Compound 65:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-nitrostyryl)oxazole;    -   Compound 66:        (E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)-3-fluoroaniline;    -   Compound 67:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-azido-2-fluorostyryl)oxazole;    -   Compound 68:        (E)-2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethyl        dimethylcarbamate;    -   Compound 69:        (E)-2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethyl        (2-methoxyethyl)carbamate;    -   Compound 70:        (E)-2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethyl        isopropylcarbamate;    -   Compound 71:        (E)-4-((1-(4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)methyl)thiomorpholine        1,1-dioxide;    -   Compound 72:        (E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)-N-(2-(5-(dimethylamino)naphthalene-1-sulfonamido)ethyl)benzamide;    -   Compound 73:        4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(5-fluoro-1H-indol-2-yl)oxazole;    -   Compound 74:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(4-(trifluoromethyl)        phenyl)prop-1-en-1-yl)oxazole;    -   Compound 75:        5-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-(trifluoromethyl)phenyl)        pyridine;    -   Compound 76:        4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(4-(trifluoromethyl)phenyl)        cyclopropyl)oxazole;    -   Compound 77: Methyl        2-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazole-4-carboxylate;    -   Compound 78:        2-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-N-(2-nitro-4-(trifluoromethyl)        phenyl)oxazole-4-carboxamide;    -   Compound 79: (E)-tert-butyl        (4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)        carbamate;    -   Compound 80:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(pyridin-4-yl)vinyl)        oxazole;    -   Compound 81:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(3-fluoropyridin-4-yl)vinyl)oxazole;    -   Compound 82:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(pyridin-3-yl)vinyl)oxazole;    -   Compound 83:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(2-fluoropyridin-3-yl)vinyl)oxazole;    -   Compound 84:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(pyridin-2-yl)vinyl)oxazole;    -   Compound 85:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(3-fluoropyridin-2-yl)vinyl)oxazole;    -   Compound 86:        (E)-3-hydroxy-N-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)        propanamide;    -   Compound 87:        (E)-3-oxo-3-((4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)        amino)propyl dimethylcarbamate;    -   Compound 88:        (E)-4-((4-(4-(1H-1,2,4-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole;    -   Compound 89:        (E)-2-(2-(4-(4-(1H-1,2,4-triazol-1-yl)butyl)phenoxy)-4-(trifluoromethyl)styryl)-4-((4-(4-(1H-1,2,4-triazol-1-yl)butyl)phenoxy)methyl)oxazole;    -   Compound 90:        (E)-4-((4-(4-(1H-tetrazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)        oxazole;    -   Compound 91:        (E)-4-((4-(4-(1H-pyrazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)        oxazole;    -   Compound 92:        (E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(4-methyl-1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)        oxazole;    -   Compound 93:        (E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(3-methyl-1H-1,2,4-triazol-1-yl)butyl)        phenoxy)methyl)oxazole;    -   Compound 94:        (E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(5-methyl-2H-tetrazol-2-yl)butyl)phenoxy)methyl)oxazole;    -   Compound 95:        (E)-2-(1-(4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethanol;    -   Compound 96:        (E)-2-(1-(4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethyl        (2-methoxyethyl)carbamate;    -   Compound 97:        (E)-2-(1-(4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethyl        cyclopentylcarbamate;    -   Compound 98:        (E)-2-(1-(4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethyl        isopropylcarbamate;    -   Compound 99:        (E)-4-((4-(4-(1H-imidazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-nitrostyryl)oxazole;    -   Compound 100:        (E)-4-((4-(4-(1H-imidazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole;    -   Compound 101:        (E)-2-(2-(4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)-4-nitrostyryl)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazole;    -   Compound 102:        (E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(pyridin-3-yl)butyl)phenoxy)methyl)oxazole;    -   Compound 103:        (E)-2-(2-fluoro-4-nitrostyryl)-4-((4-(4-(pyridin-3-yl)butyl)phenoxy)methyl)oxazole;    -   Compound 104:        (E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(pyridin-4-yl)butyl)phenoxy)methyl)oxazole;    -   Compound 105:        (E)-4-((4-(3-(1H-1,2,3-triazol-1-yl)propyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole;    -   Compound 106:        (E)-4-((4-(3-(1H-1,2,3-triazol-1-yl)propyl)phenoxy)methyl)-2-(2-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)styryl)oxazole    -   Compound 107:        (E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(thiazol-2-yl)butyl)phenoxy)methyl)        oxazole;    -   Compound 108:        (E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(pyrimidin-5-yl)butyl)phenoxy)        methyl)oxazole;    -   Compound 109:        (E)-4-((4-(3-(1H-1,2,3-triazol-1-yl)propoxy)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole;    -   Compound 110:        (E)-4-((4-(4-(2H-tetrazol-2-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole;    -   Compound 111:        4-((E)-4-(4-(1H-1,2,3-triazol-1-yl)butyl)styryl)-2-((E)-2-fluoro-4-(trifluoromethyl)styryl)        oxazole;    -   Compound 112:        4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(5-fluorobenzofuran-2-yl)        oxazole;    -   Compound 113:        4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(5-fluorobenzo[b]thiophen-2-yl)oxazole;    -   Compound 114: ethyl        (E)-1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazole-4-carboxylate;    -   Compound 115:        (E)-4-((4-((2-(1H-1,2,3-triazol-1-yl)ethoxy)methyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole;    -   Compound 116:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-chloro-2-fluorostyryl)oxazole;    -   Compound 117:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-chloro-4-fluorostyryl)oxazole;    -   Compound 118:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-chlorostyryl)oxazole;    -   Compound 119:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2,4-dichlorostyryl)oxazole;    -   Compound 120:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(3,4,5-trifluorostyryl)oxazole;    -   Compound 121:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(3,4-difluorostyryl)oxazole;    -   Compound 122:        (E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)-3-fluorobenzonitrile;    -   Compound 123:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(methylsulfonyl)styryl)oxazole;    -   Compound 124:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethoxy)styryl)oxazole;    -   Compound 125: methyl        (E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)-3-fluorobenzoate;    -   Compound 126:        4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(5-fluoro-7-nitro-1H-indol-2-yl)oxazole;    -   Compound 127:        4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(6-fluoro-1H-indol-2-yl)oxazole;    -   Compound 128:        4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4,6-difluoro-1H-indol-2-yl)oxazole;    -   Compound 129:        4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(6-nitro-1H-indol-2-yl)oxazole;    -   Compound 130:        (E)-4-((4-((3-(1H-1,2,3-triazol-1-yl)propyl)thio)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole;    -   Compound 131:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)thiazole;    -   Compound 132:        (E)-4-(((4-(3-(1H-1,2,3-triazol-1-yl)propyl)phenyl)thio)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole;    -   Compound 133:        (E)-4-(((6-(4-(1H-1,2,3-triazol-1-yl)butyl)pyridin-3-yl)oxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole;    -   Compound 134:        (E)-4-(4-(4-(1H-1,2,3-triazol-1-yl)butyl)benzyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole;    -   Compound 135:        (E)-4-((4-(4-(4H-1,2,4-triazol-4-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole;    -   Compound 136:        (E)-N-(4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)formamide;    -   Compound 137:        (E)-4-(4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)thiomorpholine        1,1-dioxide;    -   Compound 138:        (E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(pyridazin-3-yl)butyl)phenoxy)methyl)oxazole;    -   Compound 139:        (E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(pyrimidin-2-yl)butyl)phenoxy)methyl)oxazole;    -   Compound 140:        (E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(pyridin-2-yl)butyl)phenoxy)methyl)oxazole;    -   Compound 141:        (E)-4-(2-(4-((4-((3-(1H-1,2,3-triazol-1-yl)propyl)thio)phenoxy)methyl)oxazol-2-yl)vinyl)-3-fluorobenzonitrile;    -   Compound 142:        4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(6-fluorobenzofuran-2-yl)oxazole;    -   Compound 143:        4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(6-fluorobenzo[b]thiophen-2-yl)oxazole;    -   Compound 144:        4-((4-((3-(1H-1,2,3-triazol-1-yl)propyl)thio)phenoxy)methyl)-2-(4,6-difluoro-1H-indol-2-yl)oxazole;    -   Compound 145:        (E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)-5-methyloxazole;    -   Compound 146:        (E)-4-(((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenyl)thio)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole;        and    -   Compound 147:        (E)-4-((4-((2-(1H-1,2,3-triazol-1-yl)ethyl)thio)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole.

Of note, Compound 1 above corresponds to Mubritinib (CAS Number366017-09-6), also referred to as TAK-165 or(1-(4-{4-[(2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazol-4-yl)methoxy]phenyl}butyl)-1H-1,2,3-triazole,which has the following structure:

In preferred embodiments, the compound is one of the following:Compounds 1, 2, 3A, 3B, 10, 12, 17, 19, 21 to 23, 25, 27, 33, 37 to 41,45 to 48, 53 to 55, 58, 60 to 62, 65, 67, 68, 70, 71, 73, 80 to 83, 87,92, 96 to 100, 102, 103, 105, 109 to 113, 115 to 125, 127 to 131, 133,135 to 138, and 141 to 147, or a pharmaceutically acceptable saltthereof.

In more preferred embodiments, the compound is one of the following:Compounds 1, 3A, 10, 17, 19, 21, 22, 23, 25, 27, 33, 37, 38, 39, 40, 41,45, 47, 48, 53, 58, 60, 61, 65, 67, 68, 70, 71, 73, 81, 82, 83, 87, 96to 100, 103, 109 to 113, 116 to 125, 127 to 131, 133, 136, 138, and 141to 147, or a pharmaceutically acceptable salt thereof.

In other more preferred embodiments, the compound is one of thefollowing: Compounds 1, 3A, 10, 17, 21, 23, 27, 38, 40, 45, 48, 53, 65,71, 73, 81, 98, 112, 116, 120, 121, 122, 124, 125, 127, 128, 129, 130,133, 138, 141, 144, and 147, or a pharmaceutically acceptable saltthereof.

In yet more preferred embodiments, the compound is one of the following:Compounds 3A, 22, 23, 37, 48, 99, 112, 121, 122, 124, 125, 127, 128,129, and 130, or a pharmaceutically acceptable salt thereof.

In yet more preferred embodiments, the compound is one of the following:Compounds 3A, 10, 65, 71, 73, 120, 122, 124, 127, 128, 129, 130, 138,141, 144, and 147, or a pharmaceutically acceptable salt thereof.

In most preferred embodiments, the compound is one of the following:Compounds 65, 122, 124, 127, 128, 129, 130, 138, 141, 144, and 147, or apharmaceutically acceptable salt thereof.

Other aspects also relate to a compound according to any of theembodiments defined herein, with one or more of the following provisos:

-   -   provided that

does not represent

in which X³ is a covalent bond, X¹ is —N═, X⁴ is —O—, and X⁵ is —CH═;

-   -   provided that R² is not ArylC(R³)═C(H)—, wherein R³ is H and        Aryl is p-trifluoromethylphenyl;    -   provided that L¹ is not —CH₂—O—;    -   provided that X⁶ and X⁷ are not both —CH═;    -   provided that L² is not a covalent bond;    -   provided that m is not 4;    -   provided that R¹ is not

wherein R¹³ and R¹⁴ are each H; and/or

-   -   provided that the compound is not Compound 1.

Alternatively, with one or more of the following provisos:

-   -   provided that

does not represent any one, any subset, or all of the following:

in which X¹ is —N═, X³ is a covalent bond, X⁴ is —O—, and X⁵ is —CH═;and/or

in which X¹ is —CH═, X² is —CH═, X³ is —C(R²)═, X⁴ is —N═, and X⁵ is—CH═;

-   -   provided that R² does not represent any one, any subset, or all        of the following:        -   ArylC(R³)═C(H)—;        -   ArylC(R³)═C(H)—, wherein R³ is H and Aryl is            p-trifluoromethylphenyl;        -   ArylC(R³)═C(H)—, wherein R³ is H and Aryl is            p-trifluoromethoxyphenyl;        -   ArylC(R³)═C(H)—, wherein R³ is H and Aryl is            p-methoxyphenyl;        -   ArylC(R³)═C(H)—, wherein R³ is H and Aryl is p-fluorophenyl;        -   ArylC(R³)═C(H)—, wherein R³ is H and Aryl is            2,4-difluorophenyl;        -   ArylC(R³)═C(H)—, wherein R³ is H and Aryl is            2,6-difluorophenyl;        -   ArylC(R³)═C(H)—, wherein R³ is H and Aryl is phenyl;        -   ArylC(R³)═C(H)—, wherein R³ is H and Aryl is            2-fluoro-4-trifluoromethylphenyl;        -   ArylC(R³)═C(H)—, wherein R³ is H and Aryl is            3-trifluoromethylphenyl;        -   Heteroaryl, optionally substituted with one to three R⁴            groups;

wherein X⁸ is —NH— and/or X⁹ is —CH═;

-   -   -   Aryl optionally substituted with one to three R⁴ groups;        -   phenyl optionally substituted with one to three R⁴ groups;        -   p-trifluoromethylphenyl;        -   Aryl(N(R³)C(O)—; and/or        -   Aryl(N(R³)C(O)—, wherein Aryl is            2-nitro-4-trifluoromethylphenyl and R³ is H;

    -   provided that L¹ does not represent any one, any subset, or all        of the following:        -   —CH₂—O—;        -   —CH₂—NH—; and/or        -   —C(O)NH—;

    -   provided that X⁶ and X⁷ are not both —CH═;

    -   provided that L² does not represent any one, any subset, or all        of the following:        -   a covalent bond;        -   —C(O)—;        -   —C(R³)(OH)—; and/or        -   —CH(OH)—;

    -   provided that m is not 3 and/or 4;

    -   provided that R¹ does not represent any one, any subset, or all        of the following:

wherein R¹³ and R¹⁴ are each H;

wherein R¹³ and R¹⁴ are each H;

wherein R¹³ and R¹⁴ are each H and R¹⁵ is —(CH₂)₂OH;

wherein R¹³ and R¹⁴ are each H and R¹⁵ is —(CH₂)₂NH₂;

wherein R¹³ and R¹⁴ are each H and R¹⁵ is —(CH₂)₂NHSO₂CH₃; and/or

wherein R¹³ and R¹⁴ are each H and R¹⁵ is —(CH₂)₂NHSO₂CF₃; and/or

-   -   provided that the compound is not any one, any subset, or all of        the following: Compounds 1, 2, 18, 19, 26, 30, 32, 39, 45, 46,        47, 48, 49, 50, 51, 52, 54, 55, 73, 75, and/or 78.

The compound as herein defined may be in any amorphous, crystalline orpolymorphic form, including their salts and/or solvates, or acombination or mixture thereof.

The compounds described herein may be prepared by any method known to askilled medicinal chemist. Examplary methods are presented in theExamples section.

In an embodiment, the compound or pharmaceutically acceptable saltthereof inhibits leukemic cell growth (e.g., OCI-AML3 cell growth) withan EC₅₀ that is about 1 μM or less, 500 nM or less, 100 nM or less, 75nM or less, 50 nM or less, 10 nM or less, 5 nM or less, or 1 nM or less.In another embodiment, the compound or pharmaceutically acceptable saltthereof inhibits leukemic cell growth (e.g., OCI-AML3 cell growth) withan EC₅₀ that is about 100 nM or less, for example from about 100 nM toabout 1 nM. In another embodiment, the compound or pharmaceuticallyacceptable salt thereof inhibits leukemic cell growth (e.g., OCI-AML3cell growth) with an EC₅₀ that is about 50 nM or less, for example fromabout 50 nM to about 1 nM. In an embodiment, the EC₅₀ is assessed usingthe assay described in the Examples below.

iii. Methods, Uses, Formulations and Administration

Inhibitors of mitochondrial activity/respiration, such as inhibitors ofthe mitochondrial ETC complex I, have been shown to inhibit tumor growthin various cancers including lung, lymphoma, and breast cancers. Theresults described herein also show that Mubritinib andstructurally-related heterocyclic compounds inhibit the growth of AMLtumor cells.

Accordingly, in an aspect, the present disclosure provides a method forinhibiting tumor growth and/or inducing tumor cell death, said methodcomprising contacting said tumor with an effective amount of thecompound of formula I or pharmaceutically acceptable thereof asdescribed herein. The present disclosure also provides the use of thecompound of formula I or pharmaceutically acceptable thereof asdescribed herein, for inhibiting tumor growth and/or inducing tumor celldeath, or for the manufacture of a medicament for inhibiting tumorgrowth and/or inducing tumor cell death. The present disclosure alsoprovides the compound of formula I or pharmaceutically acceptablethereof as described herein, for inhibiting tumor growth and/or inducingtumor cell death. In an embodiment, the method/use is in vitro. Inanother embodiment, the method/use is in vivo.

In another aspect, the present disclosure provides a method for treatingcancer in a subject, said method comprising administering to a subjectin need thereof an effective amount of the compound of formula I orpharmaceutically acceptable thereof as described herein. The presentdisclosure also provides the use of the compound of formula I orpharmaceutically acceptable thereof as described herein, for treating asubject suffering from cancer, or for the manufacture of a medicamentfor treating a subject suffering from cancer. The present disclosurealso provides the compound of formula I or pharmaceutically acceptablethereof as described herein, for use in the treatment of a subjectsuffering from cancer.

In another aspect, the present disclosure provides a method for treatingAML, for example poor prognosis or poor risk AML, said method comprisingadministering to a subject in need thereof an effective amount of thecompound of formula I or pharmaceutically acceptable thereof asdescribed herein. The present disclosure also provides the use of thecompound of formula I or pharmaceutically acceptable thereof asdescribed herein, for treating a subject suffering from AML, for examplepoor prognosis or poor risk AML, or for the manufacture of a medicamentfor treating a subject suffering from AML, for example poor prognosis orpoor risk AML. The present disclosure also provides the compound offormula I or pharmaceutically acceptable thereof as described herein,for use in the treatment of a subject suffering from AML, for examplepoor prognosis or poor risk AML.

In another aspect, the present disclosure provides a method forinhibiting mitochondrial activity/respiration in a cell (in vitro or invivo), for example a cancer cell such as an AML cell (poor prognosis orpoor risk AML cell), said method comprising contacting the cell with aneffective amount of the compound of formula I or pharmaceuticallyacceptable thereof as described herein. The present disclosure alsoprovides the use of the compound of formula I or pharmaceuticallyacceptable thereof as described herein, for inhibiting mitochondrialactivity/respiration in a cell, or for the manufacture of a medicamentfor inhibiting mitochondrial activity/respiration in a cell. The presentdisclosure also provides the compound of formula I or pharmaceuticallyacceptable thereof as described herein, for use in the inhibition ofmitochondrial activity/respiration in a cell.

The term “inhibition of mitochondrial activity” (or “inhibition ofmitochondrial respiration”) as used herein refers to the inhibition ofthe oxidative cellular energy production process, typically theinhibition of the aerobic cell metabolism. It includes inhibition of thecellular tricarboxylic acid (TCA) cycle (also known as the citric acidcycle, CAC, or Krebs cycle) (chemical conversion of carbohydrates, fatsand proteins into carbon dioxide and water to generate a form of usableenergy), and inhibition of the cellular oxidative (aerobic) glycolysis(metabolism of glucose to pyruvate in the cell cytoplasm) or of theoxidative phosphorylation of glycolysis substrate (pyruvate). Themitochondrial activity inhibition according to the present disclosure isthe capacity to block the ETC or oxidative phosphorylation, leading tothe production of Reactive Oxygen Species (ROS, such as H₂O₂) (i.e.increase in the levels of ROS in the cells), i.e., is an ROS-inducingmitochondrial activity inhibition. The effective amount of the compoundof formula I or pharmaceutically acceptable salt thereof describedherein is an amount that is toxic to tumor cells, such as AML cells(that inhibits tumor cell proliferation and/or induces tumor cell death)but not toxic (or significantly less toxic) for normal, non-tumor cells.

In an embodiment, the compound of formula I or pharmaceuticallyacceptable salt thereof inhibits the ETC and induces the production ofROS in cells (i.e. increase the levels of ROS relative to an untreatedcells), i.e. is an ROS-inducing ETC inhibitor. The ETC (also known asthe respiratory chain) is a series of protein complexes located in theintermembrane space of the mitochondria of eukaryotic cells thattransfer electrons from electron donors to electron acceptors via redoxreactions, and couples this electron transfer with the transfer ofprotons (H⁺ ions) across a membrane, which creates an electrochemicalproton gradient that drives the synthesis of adenosine triphosphate(ATP). The components of the ETC are organized into 4 complexes(Complexes I to IV), and each complex contains several differentelectron carriers. Complex I, also known as the NADH-coenzyme Qreductase or NADH dehydrogenase) accepts electrons from NADH and servesas the link between glycolysis, the citric acid cycle, fatty acidoxidation and the ETC. Complex II, also known as succinate-coenzyme Qreductase or succinate dehydrogenase, includes succinate dehydrogenaseand serves as a direct link between the citric acid cycle and the ETC.Complexes I and II both produce reduced coenzyme Q, CoQH₂ which is thesubstrate for Complex III. Complex III, also known as coenzyme Qreductase, transfers the electrons from CoQH₂ to reduce cytochrome cwhich is the substrate for Complex IV. Finally, Complex IV, also knownas cytochrome c reductase, transfers the electrons from cytochrome c toreduce molecular oxygen into water. In an embodiment, the compound offormula I or pharmaceutically acceptable salt thereof described hereininhibits the activity of the Complex I and/or Complex III of the humanmitochondrial ETC, which are considered the major sites for ROSproduction. In a further embodiment, the compound of formula I orpharmaceutically acceptable salt thereof inhibits Complex I of the humanmitochondrial ETC. In a further embodiment, the compound of formula I orpharmaceutically acceptable salt thereof described herein is a class Acomplex I inhibitor according to the classification of Fato et al.(Biochim Biophys Acta, 2009 May; 1787(5): 384-392). The term “class Acomplex I inhibitor” as used herein refers to an inhibitor of complex Ithat induces the production of ROS in cells, i.e., is an ROS-inducingcomplex I inhibitor.

The term cancer as used herein refers to the physiological condition inmammals that is typically characterized by unregulated cellgrowth/proliferation, and includes different types of cancers includingcarcinomas, sarcomas, gliomas, leukemias (acute and chronic leukemias),lymphomas (Hodgkin's and non-Hodgkin's lymphomas), e.g., epithelialneoplasms, squamous cell neoplasms, basal cell, neoplasms, transitionalcell papillomas and carcinomas, adenomas and adenocarcinomas, adnexaland skin appendage neoplasms, mucoepidermoid neoplasms, cysticneoplasms, mucinous and serous neoplasms, ductal-, lobular and medullaryneoplasms, acinar cell neoplasms, complex epithelial neoplasms,specialized gonadal neoplasms, paragangliomas and glomus tumors, naeviand melanomas, soft tissue tumors including sarcomas, fibromatousneoplasms, myxomatous neoplasms, lipomatous neoplasms, myomatousneoplasms, complex mixed and stromal neoplasms, fibroepithelialneoplasms, synovial-like neoplasms, mesothelial neoplasms, germ cellneoplasms, trophoblastic neoplasms, mesonephromas, blood vessel tumors,lymphatic vessel tumors, osseous and chondromatous neoplasms, giant celltumors, miscellaneous bone tumors, gliomas, glioblastomas,oligodendrogliomas, neuroepitheliomatous neoplasms, meningiomas, nervesheath tumors, granular cell tumors and alveolar soft part sarcomas,other lymphoreticular neoplasms, plasma cell tumors, and mast celltumors. The cancer may be a cancer of any tissue/organ, e.g., lungcancer, breast cancer, colon cancer, skin cancer, liver cancer, or bloodcancer. In an embodiment, the cancer/tumor cells do not express theErb-B2 Receptor Tyrosine Kinase 2 (ERBB2 or HER2) protein. In anotherembodiment, the cancer is leukemia, preferably AML. In an embodiment,the cancer/tumor cells are sensitive to increased ROS levels oroxidative stress.

The studies described herein show that AML specimens more sensitive toMubritinib have certain characteristics/features, including (i) higherexpression of certain genes (see Tables 1 and 2b), notably homeobox(HOX)-network genes, relative to AML specimens more resistant toMubritinib, (ii) lower expression of certain genes (see Tables 2 and2a), relative to AML specimens more resistant to Mubritinib; (iii)certain cytogenetic or molecular risk factors, such as intermediatecytogenetic risk, Normal Karyotype (NK), high HOX status, mutated NPM1,mutated CEBPA, mutated FLT3, mutated DNA methylation genes (DNMT3A,TET2, IDH1, IDH2), mutated RUNX1, mutated WT1, mutated SRSF2,intermediate cytogenetic risk with abnormal karyotype (intern(abnK)),trisomy 8 (+8) and abnormal chr(5/7); and (iv) a higher leukemic stemcell (LSC) frequency, i.e. an LSC frequency of about 1 LSC per 1×10⁶total cells or more, relative to AML specimens more resistant.

TABLE 1 Genes overexpressed in Mubritinib sensitive versus resistant AMLspecimens (see Table 2b) HOXA5 HOXA9 PRDM16 LOC285758 HOXA3 HOXA. AS3HOXB5 HOXA11 BEND6 MIR4740 COL4A5 HOXA6 HOXB9 HOXA10. LINC00982 CYP7B1ANKR- AS D18B HOXA4 HOXA11. NKX2.3 HOXA7 HOXB. AS AS3

TABLE 2 Genes underexpressed in Mubritinib sensitive versus resistantAML specimens (see Table 2a) ORM1 SNORD116.4 MSLN MS4A2 PRG3 PRAMESNORD116. TINAGL1 SNORD116. ST18 24 20 MYZAP ZNF521 S100A16 KIRRELSNORD116. 21

Thus, in an embodiment, the subject treated by the method/use describedherein suffers from AML characterized by at least one of the followingfeatures (i.e. the tumor cells exhibit at least one of the followingfeatures): (a) high level of expression of one or more homeobox(HOX)-network genes; (b) high level of expression of one or more of thegenes depicted in Tables 1 and/or 2b; (c) low level of expression of oneor more of the genes depicted in Tables 2 and/or 2a; (d) one or more ofthe following cytogenetic or molecular risk factor: intermediatecytogenetic risk, Normal Karyotype (NK), mutated NPM1, mutated CEBPA,mutated FLT3, mutated DNA methylation genes, mutated RUNX1, mutated WT1,mutated SRSF2, intermediate cytogenetic risk with abnormal karyotype(intern(abnK)), trisomy 8 (+8) and abnormal chr(5/7); and (e) a leukemicstem cell (LSC) frequency of about 1 LSC per 1×10⁶ total cells, or more.

In another aspect, the present disclosure provides a method for treatingAML, said method comprising administering to a subject in need thereofan effective amount of the compound of formula I or pharmaceuticallyacceptable salt thereof described herein, wherein said AML has at leastone of the following features: (a) high level of expression of one ormore HOX-network genes; (b) high level of expression of one or more ofthe genes depicted in Tables 1 and/or 2b; (c) low level of expression ofone or more of the genes depicted in Tables 2 and/or 2a; (d) one or moreof the following cytogenetic or molecular risk factor: intermediatecytogenetic risk, Normal Karyotype (NK), mutated NPM1, mutated CEBPA,mutated FLT3, mutated DNA methylation genes, mutated RUNX1, mutated WT1,mutated SRSF2, intermediate cytogenetic risk with abnormal karyotype(intern(abnK)), trisomy 8 (+8) and abnormal chr(5/7); and (e) a leukemicstem cell (LSC) frequency of about 1 LSC per 1×10⁶ total cells, or more.

In another aspect, the present disclosure provides a use of the compoundof formula I or pharmaceutically acceptable salt thereof describedherein, for treating a subject suffering from AML, wherein said AML hasat least one of the features (a)-(e) defined above. In another aspect,the present disclosure provides a use of the compound of formula I orpharmaceutically acceptable salt thereof described herein, for themanufacture of a medicament for treating a subject suffering from AML,wherein said AML has at least one of the features (a)-(e) defined above.In another aspect, the present disclosure provides the compound offormula I or pharmaceutically acceptable salt thereof described hereinfor use in the treatment of a subject suffering from AML, wherein saidAML has at least one of the features (a)-(e) defined above.

In an embodiment, the subject to be treated has already been identifiedhas having one or more of the above-noted features (a)-(e). In anotherembodiment, the methods further comprise a step of identifying a subjecthaving one or more of the above-noted features, e.g., by performing asuitable assay, prior to administration of the compound of formula I orpharmaceutically acceptable salt thereof.

In another aspect, the present disclosure provides a method fordetermining a suitable therapy for a subject suffering from AML, themethod comprising determining the presence or absence of at least one offeatures (a)-(e) defined herein in an AML cell sample from the subject,wherein the presence of at least one of features (a)-(e) is indicativethat the subject is a suitable candidate for a therapy comprising thecompound of formula I or pharmaceutically acceptable salt thereofdescribed herein, and wherein the absence of features (a)-(e) isindicative that the subject is not a suitable candidate for a therapycomprising the compound of formula I or pharmaceutically acceptable saltthereof described herein, i.e. is a candidate for a therapy free of thecompound of formula I or pharmaceutically acceptable salt thereof.

In another aspect, the present disclosure provides a method for treatingpoor prognosis or poor-risk AML, said method comprising administering toa subject in need thereof an effective amount of the compound of formulaI or pharmaceutically acceptable salt thereof described herein. Inanother aspect, the present disclosure provides a use of the compound offormula I or pharmaceutically acceptable salt thereof described hereinfor treating poor prognosis or poor-risk AML in a subject. In anotheraspect, the present disclosure provides a use of the compound of formulaI or pharmaceutically acceptable salt thereof described herein for themanufacture of a medicament for treating poor prognosis or poor-risk AMLin a subject. In another aspect, the present disclosure provides thecompound of formula I or pharmaceutically acceptable salt thereofdescribed herein for use in the treatment of poor prognosis or poor-riskAML in a subject.

In another aspect, the present disclosure provides a method for treatingintermediate-risk AML, said method comprising administering to a subjectin need thereof an effective amount of the compound of formula I orpharmaceutically acceptable salt thereof described herein. In anotheraspect, the present disclosure provides a use of the compound of formulaI or pharmaceutically acceptable salt thereof described herein fortreating intermediate-risk AML in a subject.

In another aspect, the present disclosure provides a use of the compoundof formula I or pharmaceutically acceptable salt thereof describedherein for the manufacture of a medicament for treatingintermediate-risk AML in a subject. In another aspect, the presentdisclosure provides the compound of formula I or pharmaceuticallyacceptable salt thereof described herein for use in the treatment ofintermediate-risk AML in a subject.

In another aspect, the present disclosure provides a method for treatingpoor- and/or intermediate-risk AML, said method comprising administeringto a subject in need thereof an effective amount of the compound offormula I or pharmaceutically acceptable salt thereof described herein.In another aspect, the present disclosure provides a use of the compoundof formula I or pharmaceutically acceptable salt thereof describedherein for treating poor- and/or intermediate-risk AML in a subject. Inanother aspect, the present disclosure provides a use of the compound offormula I or pharmaceutically acceptable salt thereof described hereinfor the manufacture of a medicament for treating poor- and/orintermediate-risk AML in a subject. In another aspect, the presentdisclosure provides the compound of formula I or pharmaceuticallyacceptable salt thereof described herein for use in the treatment ofpoor- and/or intermediate-risk AML in a subject.

As used herein, the term “prognosis” refers to the forecast of theprobable outcome or course of AML; the patient's chance of recovery orsurvival. The terms “poor prognosis AML” or “poor-risk AML” as usedherein refer to an AML associated with long-term survival (5 years ormore) of less than about 25% or 20% based on the currently availabletherapies. Poor prognosis AML is often associated with, for example,deletion of part of chromosome 5 or 7, translocation between chromosomes9 and 11, translocation or inversion of chromosome 3, translocationbetween chromosomes 6 and 9, translocation between chromosomes 9 and 22,abnormalities of chromosome 11, FLT3 gene mutations, high EVI1expression, complex karyotype (>3 abnormalities), and high HOX-networkgenes expression.

The term “intermediate-risk AML” as used herein refers to an AML isassociated with long-term survival (5 years or more) of between about60% to about 25% based on the currently available therapies.intermediate-risk AMLs are generally not associated with favorable andparticular unfavorable cytogenetic aberrations (i.e., “uninformative”cytogenetic aberrations), and account for a significant proportion(approximately 55%) of AML patients. Examples of intermediate-risk AMLsinclude normal karyotype (NK) AML, NUP98-NSD1 fusion in AML with normalkaryotype (NK), trisomy 8 alone AML, and intermediate abnormal karyotypeAML.

In another aspect, the present disclosure provides a method for treatingAML (e.g., poor-risk or poor prognosis AML), said method comprisingadministering to a subject in need thereof an effective amount of thecompound of formula I or pharmaceutically acceptable salt thereofdescribed herein, wherein said AML exhibiting high level of expressionof one or more HOX-network genes (i.e., HOX-high AML). In anotheraspect, the present disclosure provides a use of the compound of formulaI or pharmaceutically acceptable salt thereof described herein fortreating AML (e.g., poor-risk or poor prognosis AML), said AMLexhibiting high level of expression of one or more HOX-network genes. Inanother aspect, the present disclosure provides a use of the compound offormula I or pharmaceutically acceptable salt thereof described herein,for the manufacture of a medicament for treating AML (e.g., poor-risk orpoor prognosis AML), said AML exhibiting high level of expression of oneor more HOX-network genes. In another aspect, the present disclosureprovides the compound of formula I or pharmaceutically acceptable saltthereof described herein for use in the treatment of AML (e.g.,poor-risk or poor prognosis AML), said AML exhibiting high level ofexpression of one or more HOX-network genes.

The present disclosure also provides a method for determining thelikelihood that a subject suffering from AML responds to a treatmentwith the compound of formula I or pharmaceutically acceptable saltthereof described herein, the method comprising determining whether AMLcells from said subject exhibit high level of expression of one or moreHOX-network genes, wherein high level of expression of the one or moreHOX-network genes in said AML cells is indicative that the subject has ahigh likelihood of responding to said treatment.

Deregulation of the HOX-MEIS-PBX network (HOX network) is a commonmolecular anomaly in AML patients (Lawrence, H. J. et al. Leukemia 13,1993-1999 (1999)). It is detected for example in two AML subtypes: inAML patients with normal karyotype (NK) carrying a mutation innucleophosmin gene (NK NPM1m, representing around 25% of patients) andin a subgroup of patients with chromosome translocations involving themixed lineage leukemia gene (MLL) on 11q23 (8% of patients).

The term “HOX-network gene” as used herein refers to a gene involved inthe regulatory network of transcription factor (TF) family HOX andexpressed in cells of the hematopoietic lineage. Members of the“HOX-network gene” expressed in cells of the hematopoietic lineageincludes HOX genes of clusters A, B and C, such as HOXB1, HOXB2, HOXB3,HOXB4, HOXB5, HOXB6, HOXB7, HOXB9, HOXB-AS3, HOXA1, HOXA2, HOXA3, HOXA4,HOXA5, HOXA6, HOXA7, HOXA9, HOXA10, HOXA10-AS, HOXA11, HOXA11-AS andHOXA-AS3, as well as other genes such as ME/S1 and PBX3. In anembodiment, at least one HOX-network gene is highly expressed in theAML. In an embodiment, at least 2 HOX-network genes are highly expressedin the AML. In an embodiment, at least 3 HOX-network genes are highlyexpressed in the AML. In an embodiment, at least 4 HOX-network genes arehighly expressed in the AML. In an embodiment, at least 5 HOX-networkgenes are highly expressed in the AML. In an embodiment, at least 10HOX-network genes are highly expressed in the AML. In an embodiment, atleast 15 HOX-network genes are highly expressed in the AML. In anembodiment, at least 20 HOX-network genes are highly expressed in theAML. In an embodiment, at least one of HOXA9 and HOXA10 are highlyexpressed in the AML. In an embodiment, both HOXA9 and HOXA10 are highlyexpressed in the AML. AML with high HOX gene expression defines adistinct biologic subset of AML, characterized by poor prognosis(adverse survival), intermediate risk cytogenetics, higher levels ofFLT3 expression, frequent FLT3 and NPM1 mutations, and high LSCfrequencies (see, e.g., Roche et al., Leukemia (2004) 18, 1059-1063;Kramarzova et al., Journal of Hematology & Oncology 2014 7:94). In anembodiment, the HOX-network gene(s) highly expressed in the AML is oneor more of the HOX-network genes listed in Table 1.

In an embodiment, the above-mentioned method further comprises measuringthe level of expression of one or more HOX-network genes in a samplecomprising leukemic cells from the subject, and comparing the level to areference level or control to determine whether the one or moreHOX-network genes is/are highly expressed or overexpressed in theleukemic cells, and wherein if the one or more HOX-network genes is/arehighly expressed or overexpressed in the leukemic cells, selecting thesubject for treatment with the compound of formula I or pharmaceuticallyacceptable salt thereof described herein.

The present disclosure also provides a method for treating AML, saidmethod comprising administering to a subject in need thereof aneffective amount of the compound of formula I or pharmaceuticallyacceptable salt thereof described herein, wherein said AML exhibits highlevel of expression of one or more of the genes depicted in Table 1. Inanother aspect, the present disclosure provides a use of the compound offormula I or pharmaceutically acceptable salt thereof described hereinfor treating a subject suffering from AML, wherein said AML exhibitshigh level of expression of one or more of the genes depicted inTable 1. In another aspect, the present disclosure provides a use of thecompound of formula I or pharmaceutically acceptable salt thereofdescribed herein for the manufacture of a medicament for treating asubject suffering from AML, wherein said AML exhibits high level ofexpression of one or more of the genes depicted in Table 1. In anotheraspect, the present disclosure provides the compound of formula I orpharmaceutically acceptable salt thereof described herein for use in thetreatment of a subject suffering from AML, wherein said AML exhibitshigh level of expression of one or more of the genes depicted in Table1.

The present disclosure also provides a method for determining thelikelihood that a subject suffering from AML responds to a treatmentwith the compound of formula I or pharmaceutically acceptable saltthereof described herein, the method comprising determining whether AMLcells from said subject exhibit high level of expression of one or moreof the genes depicted in Table 1, wherein high level of expression ofthe one or more genes in said AML cells is indicative that the subjecthas a high likelihood of responding to said treatment.

In an embodiment, at least one gene of Table 1 is highly expressed(overexpressed) in the AML. In an embodiment, at least 2 genes of Table1 are highly expressed in the AML. In an embodiment, at least 3 genes ofTable 1 are highly expressed in the AML. In an embodiment, at least 4genes of Table 1 are highly expressed in the AML. In an embodiment, atleast 5 genes of Table 1 are highly expressed in the AML. In anembodiment, at least 10 genes of Table 1 are highly expressed in theAML. In an embodiment, at least 1, 2, 3, 4, 5, 10, or more of the geneslisted in Table 1 are highly expressed in the AML. In an embodiment, allthe genes listed in Table 1 are highly expressed in the AML.

In an embodiment, the above-mentioned method further comprises measuringthe level of expression of one or more of the genes of Table 1 in asample comprising leukemic cells from the subject, and comparing thelevel to a reference level or control to determine whether the one ormore genes is/are highly expressed or overexpressed in the leukemiccells, and wherein if the one or more genes is/are highly expressed oroverexpressed in the leukemic cells, selecting the subject for treatmentwith the compound of formula I or pharmaceutically acceptable saltthereof described herein.

The present disclosure also provides a method for treating AML, saidmethod comprising administering to a subject in need thereof aneffective amount of the compound of formula I or pharmaceuticallyacceptable salt thereof described herein wherein said AML exhibits lowlevel of expression of one or more of the genes depicted in Table 2. Inanother aspect, the present disclosure provides a use of the compound offormula I or pharmaceutically acceptable salt thereof described hereinfor treating a subject suffering from AML, wherein said AML exhibits lowlevel of expression of one or more of the genes depicted in Table 2. Inanother aspect, the present disclosure provides a use of the compound offormula I or pharmaceutically acceptable salt thereof described hereinfor the manufacture of a medicament for treating a subject sufferingfrom AML, wherein said AML exhibits low level of expression of one ormore of the genes depicted in Table 2. In another aspect, the presentdisclosure provides the compound of formula I or pharmaceuticallyacceptable salt thereof described herein for use in the treatment of asubject suffering from AML, wherein said AML exhibits low level ofexpression of one or more of the genes depicted in Table 2.

The present disclosure also provides a method for determining thelikelihood that a subject suffering from AML responds to a treatmentwith the compound of formula I or pharmaceutically acceptable saltthereof described herein, the method comprising determining whether AMLcells from said subject exhibit low level of expression of one or moreof the genes depicted in Table 2, wherein low level of expression of theone or more genes in said AML cells is indicative that the subject has ahigh likelihood of responding to said treatment.

In an embodiment, at least one gene of Table 2 is weakly expressed(underexpressed) in the AML. In an embodiment, at least 2 genes of Table2 are weakly expressed in the AML. In an embodiment, at least 3 genes ofTable 2 are weakly expressed in the AML. In an embodiment, at least 4genes of Table 2 are weakly expressed in the AML. In an embodiment, atleast 5 genes of Table 2 are weakly expressed in the AML. In anembodiment, at least 10 genes of Table 2 are weakly expressed in theAML. In an embodiment, all the above-noted genes are upregulated in theAML.

In an embodiment, at least 1, 2, 3, 4, 5, 10, or more of the geneslisted in Table 2 are weakly expressed in the AML.

In an embodiment, all the genes listed in Table 2 are weakly expressedin the AML.

In an embodiment, the above-mentioned method further comprises measuringthe level of expression of one or more of the genes of Table 2 in asample comprising leukemic cells from the subject, and comparing thelevel to a reference level or control to determine whether the one ormore genes is/are weakly expressed or underexpressed in the leukemiccells, and wherein if the one or more genes is/are weakly expressed orunderexpressed in the leukemic cells, selecting the subject fortreatment with the compound of formula I or pharmaceutically acceptablesalt thereof.

The determination of the expression of the one or more genes or encodedgene products (e.g., mRNA, protein) disclosed herein (e.g., HOX-networkgenes, the genes in Tables 1 to 3) may be performed using any knownmethods to detect nucleic acids or proteins. In embodiments, theexpression is compared to a control or reference level (e.g., the levelobtained a sample from an AML subjects known to be resistant orsensitive to the compound of formula I or pharmaceutically acceptablesalt thereof to assess the subject's likelihood of responding to thecompound of formula I or pharmaceutically acceptable salt thereofdescribed herein and to determine whether the subject may be treatedwith the compound of formula I or pharmaceutically acceptable saltthereof.

The levels of nucleic acids corresponding to the above-mentioned genes(e.g., transcripts) can then be evaluated according to commonly usedmethods such as those disclosed below, e.g., with or without the use ofnucleic acid amplification methods. In some embodiments, nucleic acidamplification methods can be used to detect the level of expression ofthe one or more genes. For example, oligonucleotide primers and/orprobes may be used in amplification and detection methods that usenucleic acid substrates isolated by any of a variety of well-known andestablished methodologies (e.g., Sambrook et al., supra; Lin et al., inDiagnostic Molecular Microbiology, Principles and Applications, pp.605-16 (Persing et al., eds. (1993); Ausubel et al., Current Protocolsin Molecular Biology (2001 and later updates thereto)). Methods foramplifying nucleic acids include, but are not limited to, for examplethe polymerase chain reaction (PCR) and reverse transcription PCR(RT-PCR) (see e.g., U.S. Pat. Nos. 4,683,195; 4,683,202; 4,800,159;4,965,188), ligase chain reaction (LCR) (see, e.g., Weiss, Science 254:1292-93 (1991)), strand displacement amplification (SDA) (see e.g.,Walker et al., Proc. Natl. Acad. Sci. USA 89:392-396 (1992); U.S. Pat.Nos. 5,270,184 and 5,455,166), Thermophilic SDA (tSDA) (see e.g.,European Pat. No. 0 684 315) and methods described in U.S. Pat. No.5,130,238; Lizardi et al., BioTechnol. 6:1197-1202 (1988); Kwoh et al.,Proc. Natl. Acad. Sci. USA 86:1173-77 (1989); Guatelli et al., Proc.Natl. Acad. Sci. USA 87:1874-78 (1990); U.S. Pat. Nos. 5,480,784;5,399,491; U.S. Publication No. 2006/46265. The methods include the useof Transcription Mediated Amplification (TMA), which employs an RNApolymerase to produce multiple RNA transcripts of a target region (see,e.g., U.S. Pat. Nos. 5,480,784; 5,399,491 and U.S. Publication No.2006/46265). The levels of nucleic acids may also be measured by “NextGeneration Sequencing” (NGS) methods such as RNA sequencing (RNA-seq).In an embodiment, the method for measuring the level of expression ofthe one or more genes comprises a step of nucleic acid amplification.

The nucleic acid or amplification product may be detected or quantifiedby hybridizing a probe (e.g., a labeled probe) to a portion of thenucleic acid or amplified product. The primers and/or probes may belabelled with a detectable label that may be, for example, a fluorescentmoiety, chemiluminescent moiety, radioisotope, biotin, avidin, enzyme,enzyme substrate, or other reactive groups. As used herein, the term“detectable label” refers to a moiety emitting a signal (e.g., light)that may be detected using an appropriate detection system. Any suitabledetectable label may be used in the method described herein. Detectablelabels include, for example, enzyme or enzyme substrates, reactivegroups, chromophores such as dyes or colored particles, luminescentmoieties including bioluminescent, phosphorescent, or chemiluminescentmoieties, and fluorescent moieties. In an embodiment, the detectablelabel is a fluorescent moiety.

Other well-known detection techniques include, for example, gelfiltration, gel electrophoresis and visualization of the amplicons, andHigh-Performance Liquid Chromatography (HPLC). In certain embodiments,for example using real-time TMA or real-time PCR, the level of amplifiedproduct is detected as the product accumulates. In an embodiment, themethod for measuring the level of expression of the one or more genescomprises a step of detection or quantification of a nucleic acid oramplification product with a probe.

In an embodiment, the above-mentioned method comprises a step ofnormalizing the gene expression levels, i.e. normalization of themeasured levels of the above-noted genes against a stably expressedcontrol gene (or housekeeping gene) to facilitate the comparison betweendifferent samples. “Normalizing” or “normalization” as used hereinrefers to the correction of raw gene expression values/data betweendifferent samples for sample to sample variations, to take into accountdifferences in “extrinsic” parameters such as cellular input, nucleicacid (RNA) or protein quality, efficiency of reverse transcription (RT),amplification, labeling, purification, etc., i.e. differences not due toactual “intrinsic” variations in gene expression by the cells in thesamples. Such normalization is performed by correcting the raw geneexpression values/data for a test gene (or gene of interest) based onthe gene expression values/data measured for one or more “housekeeping”or “control” genes, i.e., whose expressions are known to be constant(i.e. to show relatively low variability) between the cells of differenttissues and under different experimental conditions.

Thus, in an embodiment, the above-mentioned method further comprisesmeasuring the level of expression of a housekeeping gene in thebiological sample. Suitable housekeeping genes are known in the art andseveral examples are described in WO 2014/134728.

In an embodiment, the method for measuring the level of expression ofthe one or more genes further comprises measuring the level ofexpression of one or more housekeeping genes in a biological sample fromthe subject.

In another embodiment, the expression of the one or more genes orencoded gene products is measured at the protein level. Methods tomeasure the amount/level of proteins are well known in the art. Proteinlevels may be detected directly using a ligand binding specifically tothe protein, such as an antibody or a fragment thereof. In embodiments,such a binding molecule or reagent (e.g., antibody) islabeled/conjugated, e.g., radio-labeled, chromophore-labeled,fluorophore-labeled, or enzyme-labeled to facilitate detection andquantification of the complex (direct detection).

Alternatively, protein levels may be detected indirectly, using abinding molecule or reagent, followed by the detection of the[protein/binding molecule or reagent] complex using a second ligand (orsecond binding molecule) specifically recognizing the binding moleculeor reagent (indirect detection). Such a second ligand may beradio-labeled, chromophore-labeled, fluorophore-labeled, orenzyme-labeled to facilitate detection and quantification of thecomplex.

Enzymes used for labeling antibodies for immunoassays are known in theart, and the most widely used are horseradish peroxidase (HRP) andalkaline phosphatase (AP). Examples of binding molecules or reagentsinclude antibodies (monoclonal or polyclonal), natural or syntheticligands, and the like. Examples of methods to measure the amount/levelof protein in a sample include, but are not limited to: Western blot,immunoblot, enzyme-linked immunosorbent assay (ELISA), “sandwich”immunoassays, radioimmunoassay (RIA), immunoprecipitation, surfaceplasmon resonance (SPR), chemiluminescence, fluorescent polarization,phosphorescence, immunohistochemical (IHC) analysis, matrix-assistedlaser desorption/ionization time-of-flight (MALDI-TOF) massspectrometry, microcytometry, microarray, antibody array, microscopy(e.g., electron microscopy), flow cytometry, proteomic-based assays, andassays based on a property or activity of the protein including but notlimited to ligand binding or interaction with other protein partners,enzymatic activity, fluorescence. For example, if the protein ofinterest is a kinase known to phosphorylate of given target, the levelor activity of the protein of interest may be determined by themeasuring the level of phosphorylation of the target in the presence ofthe test compound. If the protein of interest is a transcription factorknown to induce the expression of one or more given target gene(s), thelevel or activity of the protein of interest may be determined by themeasuring the level of expression of the target gene(s).

“Control level” or “reference level” are used interchangeably herein andbroadly refers to a separate baseline level measured in a comparable“control” sample, which is generally from a subject having a known levelof expression of the gene of interest and/or whose responsiveness to thecompound of formula I or pharmaceutically acceptable salt thereof isknown, for example an AML sample from a subject known to not respond tothe compound of formula I or pharmaceutically acceptable salt thereof.The corresponding control level may be a level corresponding to anaverage or median level calculated based of the levels measured inseveral reference or control subjects (e.g., a pre-determined orestablished standard level). The control level may be a pre-determined“cut-off” value recognized in the art or established based on levelsmeasured in samples from one or a group of control subjects (e.g., agroup of subjects known to not respond to the compound of formula I orpharmaceutically acceptable salt thereof). For example, the “thresholdreference level” may be the level corresponding the minimal level ofexpression (cut-off) of the gene(s) that permits to distinguish in astatistically significant manner AML subjects who are likely to respondto the compound of formula I or pharmaceutically acceptable salt thereofdescribed herein (sensitive) from those who are unlikely to respond tothe compound of formula I or pharmaceutically acceptable salt thereofdescribed herein (resistant), which may be determined using samples fromAML patients with different pharmalogical responses to the compound offormula I or pharmaceutically acceptable salt thereof described herein,for example. Alternatively, the “threshold reference level” may be thelevel corresponding the level of gene expression (cut-off) that permitsto best or optimally distinguish in a statistically significant mannerAML subjects sensitive to the compound of formula I or pharmaceuticallyacceptable salt thereof from AML subjects resistant a mitochondriaactivity inhibitor (e.g., Mubritinib). The correspondingreference/control level may be adjusted or normalized for age, gender,race, or other parameters. The “control level” can thus be a singlenumber/value, equally applicable to every subject individually, or thecontrol level can vary, according to specific subpopulations ofpatients. Thus, for example, older men might have a different controllevel than younger men, and women might have a different control levelthan men. The predetermined standard level can be arranged, for example,where a tested population is divided equally (or unequally) into groups,such as a low-likelihood group, a medium-likelihood group and/or ahigh-likelihood group or into quadrants or quintiles. It will also beunderstood that the control levels may be, in addition to predeterminedlevels or standards, levels measured in other samples (e.g., from asubject having a known level of expression of the gene of interestand/or whose responsiveness to the compound of formula I orpharmaceutically acceptable salt thereof is known) tested in parallelwith the experimental sample. The reference or control levels maycorrespond to normalized levels, i.e. reference or control valuessubjected to normalization based on the expression of a housekeepinggene.

“Higher expression” or “higher level of expression” (overexpression) asused herein refers to (i) higher expression of the one or more of theabove-mentioned genes (protein and/or mRNA) in one or more given cellspresent in the sample (relative to the control) and/or (ii) higheramount of cells expressing the one or more genes in the sample (relativeto the control). “Low/weak expression” or “lower/weaker level ofexpression” (underexpression) as used herein refers to (i) lowerexpression of the one or more genes (protein and/or mRNA) in one or moregiven cells present in the sample (relative to the control) and/or (ii)lower amount of cells expressing the one or more genes in the sample(relative to the control). In an embodiment, higher or lower refers to alevel of expression that is above or below the control level (e.g., thepredetermined cut-off value). In another embodiment, higher or lowerrefers to a level of expression that is at least one standard deviationabove or below the control level (e.g., the predetermined cut-off value)(e.g., that is statistically significant as determined using a suitablestatistical analysis), and a “similar expression” or “similar level ofexpression” refers to a level of expression that is less than onestandard deviation above or below the control level (e.g., thepredetermined cut-off value) (e.g., that is not statisticallysignificant as determined using a suitable statistical analysis, such asFalse Discovery Rate (FDR)/q-values, Student t-test/p values,Mann-Whitney test/p values). In embodiments, higher or lower refers to alevel of expression that is at least 1.5, 2, 2.5, 3, 4 or 5 standarddeviations above or below the control level (e.g., the predeterminedcut-off value. In another embodiment, “higher expression” refers to anexpression that is at least 10, 20, 30, 40, 45 or 50% higher in the testsample relative to the control level. In an embodiment, “lowerexpression” refers to an expression that is at least 10, 20, 25, 30, 35,40, 45, or 50% lower in the test sample relative to the control level.In another embodiment, higher or lower refers to a level of expressionthat is at least 1.5, 2-, 5-, 10-, 25-, or 50-fold higher or lower inthe test sample relative to the control sample.

In another aspect, the present disclosure provides a method for treatingAML, said method comprising administering to a subject in need thereofan effective amount of the compound of formula I or pharmaceuticallyacceptable salt thereof described herein, wherein said AML exhibits oneor more of the following cytogenetic or molecular risk factor: NormalKaryotype (NK), mutated NPM1, mutated CEBPA (e.g., mono- or bi-allelic),mutated FLT3, mutated DNMT3A, mutated TET2, mutated IDH1, mutated IDH2,mutated RUNX1, mutated WT1, mutated SRSF2, intermediate cytogeneticrisk, intermediate cytogenetic risk with abnormal karyotype(intern(abnK)), trisomy 8 (+8) and abnormal chr(5/7). In another aspect,the present disclosure provides a use of the compound of formula I orpharmaceutically acceptable salt thereof described herein for treating asubject suffering from AML, wherein said AML exhibits one or more of theabove-noted cytogenetic or molecular risk factors. In another aspect,the present disclosure provides a use of the compound of formula I orpharmaceutically acceptable salt thereof described herein for themanufacture of a medicament for treating a subject suffering from AML,wherein said AML exhibits one or more of the above-noted cytogenetic ormolecular risk factors. In another aspect, the present disclosureprovides the compound of formula I or pharmaceutically acceptable saltthereof described herein for use in the treatment of AML, wherein saidAML exhibits one or more of the above-noted cytogenetic or molecularrisk factors.

In an embodiment, the subject suffers from AML characterized byintermediate cytogenetic risk, Normal Karyotype (NK), and/or high HOXexpression. In an embodiment, the subject suffers from AML withintermediate cytogenetic risk.

In an embodiment, the subject suffers from AML with Normal Karyotype(NK). In an embodiment, the subject suffers from AML with high HOXexpression.

The present disclosure also provides a method for determining thelikelihood that a subject suffering from AML responds to a treatment thecompound of formula I or pharmaceutically acceptable salt thereofdescribed herein, the method comprising determining whether AML cellsfrom said subject exhibit one or more of the following cytogenetic ormolecular risk factor: Normal Karyotype (NK), mutated NPM1, mutatedCEBPA, mutated FLT3, mutated DNMT3A, mutated TET2, mutated IDH1, mutatedIDH2, mutated RUNX1, mutated WT1, mutated SRSF2, intermediatecytogenetic risk, intermediate cytogenetic risk with abnormal karyotype(intern(abnK)), trisomy 8 (+8) and abnormal chr(5/7), wherein thepresence of said one or more of cytogenetic or molecular risk factor insaid AML cells is indicative that the subject has a high likelihood ofresponding to said treatment. In an embodiment, the mutation in theabove-noted mutated genes is at one or more of the positions depicted inTable 3B. In a further embodiment, the mutation in the above-notedmutated genes is one or more of the mutations depicted in Table 3B.

In an embodiment, the method/use is for treating NK-AML. In anembodiment, the method/use is for treating AML with mutated FLT3 (e.g.,FLT3 with internal tandem duplications, FLT3-ITD). In an embodiment, themethod/use is for treating AML with mutated CEBPA. In an embodiment, themethod/use is for treating AML with mutated DNMT3A. In an embodiment,the method/use is for treating AML with mutated TET2. In an embodiment,the method/use is for treating AML with mutated IDH1. In an embodiment,the method/use is for treating AML with mutated IDH2. In an embodiment,the method/use is for treating AML with mutated RUNX1. In an embodiment,the method/use is for treating AML with mutated WT1. In an embodiment,the method/use is for treating AML with mutated SRSF2. In an embodiment,the method/use is for treating AML with intermediate cytogenetic riskwith abnormal karyotype (intern(abnK)). In an embodiment, the method/useis for treating AML with trisomy 8 (+8). In an embodiment, themethod/use is for treating AML with abnormal chromosome (5/7).

In an embodiment, the method is for treatment AML with any combinationof 2, 3, 4, 5 or more of the above-mentioned cytogenetic or molecularrisk factors.

In an embodiment, the AML is not AML with MLL translocations. In anembodiment, the AML is not EV/1-rearranged AML. In an embodiment, theAML is not Core Binding Factor (CBF) AML, for example AML with t(8:21)or inv(16) chromosomal rearrangements. In an embodiment, the AML is notAML with mutated NRAS, mutated c-KIT and/or mutated TP53.

In an embodiment, the AML is NK-AML with mutated NPM1. In an embodiment,the AML cells comprise a mutated NPM1, a mutated FLT3 (e.g., FLT3 withinternal tandem duplications, FLT3-ITD) and a mutated DNA methylationgene such as DNMT3A. In a further embodiment, the AML cells comprise amutated NPM1, a mutated FLT3 (e.g., FLT3 with internal tandemduplications, FLT3-ITD), a mutated DNA methylation gene such as DNMT3A,and do not comprise a mutated NRAS.

The cytogenetic and molecular risk factors defined herein are based onthe 2008 World Health Organization (WHO) classification (Vardiman etal., Blood 2009 114:937-951), and recent advances in genomicclassification (Papaemmanuil, E. et al. N Engl J Med 374, 2209-2221,2016).

In another embodiment, the above-noted method/use further comprisesdetermining the presence (or absence) of one or more of the cytogeneticand molecular risk factors defined herein in a sample comprisingleukemic cells from the subject, wherein if one or more of thecytogenetic and molecular risk factors are present, selecting thesubject for treatment with the compound of formula I or pharmaceuticallyacceptable salt thereof described herein.

Methods and kits to identify cytogenetic or molecular risk factors(mutation(s), translocations, fusions, chromosomal abnormalities, etc.)are well known in the art, and include, for example, karyotype,fluorescence in situ hybridization (FISH), reverse transcriptionpolymerase chain reaction (RT-PCR), DNA sequencing, and microarraytechnology (see, e.g., Gulley et al., J Mol Diagn. 2010 January; 12(1):3-16). The determination of the presence of the mutation(s),translocations, fusions, etc. in the sample may be performed using anysuitable methods (see, e.g., Syvänen, Nat Rev Genet. 2001 Dec.;2(12):930-42). For example, the presence of the mutation(s) may bedetected at the genomic DNA, transcript (RNA or cDNA) or protein level.Examples of suitable methods for determining sequences and polymorphismsat the nucleic acid level include sequencing of the nucleic acidsequence encompassing the mutation(s), e.g., in the genomic DNA ortranscript (cDNA), for example by “Next Generation Sequencing” methods(e.g., genome sequencing, RNA sequencing (RNA-seq)) or other sequencingmethods; hybridization of a nucleic acid probe capable of specificallyhybridizing to a nucleic acid sequence comprising the mutation(s) andnot to (or to alesser extent to) a corresponding nucleic acid sequencethat does not comprises the mutation(s) (under comparable hybridizationconditions, such as stringent hybridization conditions) (e.g., molecularbeacons); restriction fragment length polymorphism analysis (RFLP);Amplified fragment length polymorphism PCR (AFLP-PCR); amplification ofa nucleic acid fragment comprising the mutation(s) using a primerspecifically hybridizing to a nucleic acid sequence comprising themutation(s), wherein the primer produces an amplified product if themutation(s) is/are present and does not produce the same amplifiedproduct when a nucleic acid sequence not comprising the mutation(s) isused as a template for amplification, nucleic acid sequence basedamplification (Nasba), primer extension assay, FLAP endonuclease assay(Invader assay, Olivier M. (2005). Mutat Res. 573(1-2):103-10),5′-nuclease assay (McGuigan F. E. and Ralston S. H. (2002) PsychiatrGenet. 12(3):133-6), oligonucleotide ligase assay. Other methods includein situ hybridization analyses and single-stranded conformationalpolymorphism analyses. Several SNP genotyping platforms are commerciallyavailable. Additional methods will be apparent to one of skill in theart.

The determination of the presence of the mutation(s) and/or fusion(s)may also be achieved at the polypeptide/protein level. Examples ofsuitable methods for detecting alterations at the polypeptide levelinclude sequencing of the encoded polypeptide; digestion of the encodedpolypeptide followed by mass spectrometry or HPLC analysis of thepeptide fragments, wherein the mutated polypeptide results in an alteredmass spectrometry or HPLC spectrum as compared to the unmutatedpolypeptide; and immunodetection using an immunological reagent (e.g.,an antibody, a ligand) which exhibits altered immunoreactivity with amutated polypeptide relative to a corresponding unmutated polypeptide.

Immunodetection can measure the amount of binding between a polypeptidemolecule and an anti-protein antibody by the use of enzymatic,chromodynamic, radioactive, magnetic, or luminescent labels which areattached to either the anti-protein antibody or a secondary antibodywhich binds the anti-protein antibody. In addition, other high affinityligands may be used. Immunoassays which can be used include e.g.,ELISAs, Western blots, and other techniques known to those of ordinaryskill in the art (see Harlow and Lane, Antibodies: A Laboratory Manual,Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1999 andEdwards R, Immunodiagnostics: A Practical Approach, Oxford UniversityPress, Oxford; England, 1999).

All these detection techniques may also be employed in the format ofmicroarrays, e.g., SNP microarrays, DNA microarrays, protein-arrays,antibody microarrays, tissue microarrays, electronic biochip orprotein-chip based technologies (see Schena M., Microarray BiochipTechnology, Eaton Publishing, Natick, Mass., 2000).

In another embodiment, the methods described herein to identify thepresence of one or more features in the AML cells further compriseobtaining or collecting a biological sample from a subject. In variousembodiments, the sample can be from any source that contains biologicalmaterial suitable for the detection of the mutation(s), such as genomicDNA, RNA (cDNA), and/or proteins, for example a tissue or cell samplefrom the subject (blood cells, immune cells (e.g., lymphocytes), etc.that comprises cancer cells, such as leukemic cells (e.g., AML cells).The sample may be subjected to cell purification/enrichment techniquesto obtain a cell population enriched in a specific cell subpopulation orcell type(s). The sample may be subjected to commonly used isolationand/or purification techniques for enrichment in nucleic acids (genomicDNA, cDNA, mRNA) and/or proteins. Accordingly, in an embodiment, themethod may be performed on an isolated nucleic acid and/or proteinsample, such as isolated genomic DNA. The biological sample may becollected using any methods for collection of biological fluid, tissueor cell sample, such as venous puncture for collection of blood cellsamples.

The present disclosure also provides a method for treating AML, saidmethod comprising administering to a subject in need thereof aneffective amount of the compound of formula I or pharmaceuticallyacceptable salt thereof described herein, wherein said AML exhibits aleukemic stem cell (LSC) frequency of about 1 LSC per 1×10⁶ total cells,or more.

The present disclosure also provides a method for determining thelikelihood that a subject suffering from AML responds to a treatmentwith the compound of formula I or pharmaceutically acceptable saltthereof described herein, the method comprising determining LSCfrequency in the AML cells from said subject, wherein an LSC frequencyof about 1 LSC per 1×10⁶ total cells, or more, is indicative that thesubject has a high likelihood of responding to said treatment.

In an embodiment, the AML exhibits an LSC frequency of about 1 LSC per9×10⁵ total cells, or more. In an embodiment, the AML exhibits an LSCfrequency of about 1 LSC per 8×10⁵ total cells, or more. In anembodiment, the AML exhibits an LSC frequency of about 1 LSC per 7×10⁵total cells, or more. In an embodiment, the AML exhibits an LSCfrequency of about 1 LSC per 6×10⁵ total cells, or more. In anembodiment, the AML exhibits an LSC frequency of about 1 LSC per 5×10⁵total cells, or more. In an embodiment, the AML exhibits an LSCfrequency of about 1 LSC per 4×10⁵ total cells, or more. In anembodiment, the AML exhibits an LSC frequency of about 1 LSC per 3×10⁵total cells, or more. In an embodiment, the AML exhibits an LSCfrequency of about 1 LSC per 2×10⁵ total cells, or more. In anembodiment, the AML exhibits an LSC frequency of about 1 LSC per 1×10⁵total cells, or more.

LSC frequency in an AML cell sample may be measured using methods knownin the art, for example using a flow cytometric-based assay usingLSC-associated markers (CD34+CD38-) and light scatter aberrancies(Terwijn et al., PLoS One. 2014 Sep. 22; 9(9):e107587) or using alimiting dilution assay (LDA) in a model of xenotransplantation based onNOD/SCID/lL2Ryc-deficient (NSG) mice (Sarry et al., J Clin Invest. 2011;121(1):384-395; Pabst, C. et al. Blood 127, 2018-2027 and US PatentPublication No. 2014/0343051 A1)), as used in the studies describedbelow. In an embodiment, the LSC frequency is as measured using thelimiting dilution assay in NSG mice described in the Examples below.

In an embodiment, the above-mentioned method further comprises measuringthe LSC frequency in a sample comprising leukemic cells from thesubject, and wherein if the LSC frequency is about 1 LSC per 1×10⁶ totalcells, or more, selecting the subject for treatment with the compound offormula I or pharmaceutically acceptable salt thereof described herein.

In another aspect, the present disclosure provides a method fordetermining whether a subject suffering from cancer AML is likely torespond to a treatment with the compound of formula I orpharmaceutically acceptable salt thereof, said method comprisingdetermining whether the AML has at least one of the following features:(a) high level of expression of one or more homeobox (HOX)-networkgenes; (b) high level of expression of one or more of the genes depictedin Table 1; (c) low level of expression of one or more of the genesdepicted in Table 2; (d) one or more of the following cytogenetic ormolecular risk factor: intermediate cytogenetic risk, Normal Karyotype(NK), mutated NPM1, mutated CEBPA, mutated FLT3, mutated DNA methylationgenes, mutated RUNX1, mutated WT1, mutated SRSF2, intermediatecytogenetic risk with abnormal karyotype (intern(abnK)), trisomy 8 (+8)and abnormal chr(5/7); and (e) a leukemic stem cell (LSC) frequency ofabout 1 LSC per 1×10⁶ total cells, or more; wherein the presence of atleast one of these features in said AML is indicative that the patientis likely to respond to a treatment with the compound of formula I orpharmaceutically acceptable salt thereof.

Methods to measure the above-noted features are well known in the art,and representative methods are described above.

In another embodiment, the compound of formula I or pharmaceuticallyacceptable salt thereof described herein is administered/used as aprodrug, for example as a pharmaceutically acceptable ester. The term“prodrug” refers to analogs of an active agent (compound of formula I orpharmaceutically acceptable salt thereof) that are pharmacologicallyacceptable and substantially non-toxic to the subject to which they areadministered. More specifically, the prodrug retains the biologicaleffectiveness and properties of the active agent and when absorbed intothe bloodstream of a warm-blooded animal, is cleaved or metabolized insuch a manner as to produce the parent active agent. Methods to produceprodrugs of compounds are known in the art.

In the methods/uses of the present disclosure, the compound of formula Ior pharmaceutically acceptable salt thereof may be administered usingany conventional route, for example orally, intravenously, parenterally,subcutaneously, intramuscularly, intraperitoneally, intranasally orpulmonary (e.g., aerosol).

In an embodiment, the above-mentioned treatment comprises theuse/administration of more than one (i.e. a combination of)active/therapeutic agent or therapy, one of which being with thecompound of formula I or pharmaceutically acceptable salt thereof. Thecombination of prophylactic/therapeutic agents and/or compositions ofthe present disclosure may be administered or co-administered (e.g.,consecutively, simultaneously, at different times) in any conventionaldosage form. Co-administration in the context of the present disclosurerefers to the administration of more than one therapeutic in the courseof a coordinated treatment to achieve an improved clinical outcome. Suchco-administration may also be coextensive, that is, occurring duringoverlapping periods of time. For example, a first agent (e.g., thecompound of formula I or pharmaceutically acceptable salt thereof) maybe administered to a patient before, concomitantly, before and after, orafter a second active agent or therapy is administered. In anembodiment, the one or more active agent(s) is used/administered incombination with one or more agent(s) currently used to prevent or treatthe disorder in question, for example chemotherapeutic drugs used forthe treatment of cancers such as AML. The compound of formula I orpharmaceutically acceptable salt thereof may also be used in combinationwith one or more other cancer therapies, for example stem cell/bonemarrow transplantation, radiation and/or surgery.

In an embodiment, the compound of Formula I or pharmaceuticallyacceptable salt thereof is present in a pharmaceutical composition.Thus, in another aspect, the present technology provides a compositionfor use in the treatment of AML in a subject, the composition comprisingthe compound of formula I or pharmaceutically acceptable salt thereof.

In an embodiment, the composition comprises one or more pharmaceuticallyacceptable carriers or excipients. Supplementary active compounds canalso be incorporated into the compositions. The carrier/excipient can besuitable, for example, for intravenous, parenteral, subcutaneous,intramuscular, intraperitoneal, intranasal or pulmonary (e.g., aerosol)administration (see Remington: The Science and Practice of Pharmacy, byLoyd V Allen, Jr, 2012, 22^(nd) edition, Pharmaceutical Press; Handbookof Pharmaceutical Excipients, by Rowe et al., 2012, 7^(th) edition,Pharmaceutical Press). Pharmaceutical compositions may be prepared usingstandard methods known in the art by mixing the Mubritinib orpharmaceutically acceptable salt thereof having the desired degree ofpurity with one or more optional pharmaceutically acceptable carriersand/or excipients.

The term “pharmaceutically acceptable carrier or excipient” as usedherein has its normal meaning in the art and refers any ingredient thatis not an active ingredient (mitochondrial activity inhibitor such asMubritinib or pharmaceutically acceptable salt thereof) itself that doesnot interfere with effectiveness of the biological activity of theactive ingredient and that is not toxic to the subject, i.e., is a typeof carrier or excipient and/or is for use in an amount which is nottoxic to the subject. Excipients/carriers include for example binders,lubricants, diluents, fillers, thickening agents,disintegrants/dissolution promoting agents, plasticizers, coatings,barrier layer formulations, lubricants, surfactants, stabilizing agent,release-delaying agents, permeation enhancers, glidants, anti-cakingagents, anti-tacking agents, stabilizing agents, anti-static agents,swelling agents and other components. As those of skill would recognize,a single excipient can fulfill more than two functions at once, e.g.,can act as both a binding agent and a thickening agent. As those ofskill will also recognize, these terms are not necessarily mutuallyexclusive.

Useful diluents, e.g., fillers, include, for example and withoutlimitation, dicalcium phosphate, calcium diphosphate, calcium carbonate,calcium sulfate, lactose, cellulose, kaolin, sodium chloride, starches,powdered sugar, colloidal silicon dioxide, titanium oxide, alumina,talc, colloidal silica, microcrystalline cellulose, silicified microcrystalline cellulose and combinations thereof. Fillers that can addbulk to tablets with minimal drug dosage to produce tablets of adequatesize and weight include croscarmellose sodium NF/EP (e.g., Ac-Di-Sol™);anhydrous lactose NF/EP (e.g., Pharmatose™ DCL 21); and/or povidoneUSP/EP.

Binder materials include, for example and without limitation, starches(including corn starch and pregelatinized starch), gelatin, sugars(including sucrose, glucose, dextrose and lactose), polyethylene glycol,povidone, waxes, and natural and synthetic gums, e.g., acacia sodiumalginate, polyvinylpyrrolidone, cellulosic polymers (e.g., hydroxypropylcellulose, hydroxypropyl methylcellulose, methyl cellulose, hydroxyethylcellulose, carboxymethylcellulose, colloidal silicon dioxide NF/EP(e.g., Cab-O—Sil™ M5P), Silicified Microcrystalline Cellulose (SMCC),e.g., Silicified microcrystalline cellulose NF/EP (e.g., Prosolv™ SMCC90), and silicon dioxide, mixtures thereof, and the like), veegum, andcombinations thereof.

Useful lubricants include, for example, canola oil, glycerylpalmitostearate, hydrogenated vegetable oil (type I), magnesium oxide,magnesium stearate, mineral oil, poloxamer, polyethylene glycol, sodiumlauryl sulfate, sodium stearate fumarate, stearic acid, talc and, zincstearate, glyceryl behapate, magnesium lauryl sulfate, boric acid,sodium benzoate, sodium acetate, sodium benzoate/sodium acetate (incombination), dl-leucine, calcium stearate, sodium stearyl fumarate,mixtures thereof, and the like.

Bulking agents include, for example: microcrystalline cellulose, forexample, AVICEL® (FMC Corp.) or EMCOCEL® (Mendell Inc.), which also hasbinder properties; dicalcium phosphate, for example, EMCOMPRESS®(Mendell Inc.); calcium sulfate, for example, COMPACTROL® (MendellInc.); and starches, for example, Starch 1500; and polyethylene glycols(CARBOWAX®).

Disintegrating or dissolution promoting agents include: starches, clays,celluloses, alginates, gums, crosslinked polymers, colloidal silicondioxide, osmogens, mixtures thereof, and the like, such as crosslinkedsodium carboxymethyl cellulose (AC-DI-SOL®), sodium croscarmelose,sodium starch glycolate (EXPLOTAB®, PRIMO JEL®) crosslinkedpolyvinylpolypyrrolidone (PLASONE-XL®), sodium chloride, sucrose,lactose and mannitol.

Antiadherents and glidants employable in the core and/or a coating ofthe solid oral dosage form may include talc, starches (e.g.,cornstarch), celluloses, silicon dioxide, sodium lauryl sulfate,colloidal silica dioxide, and metallic stearates, among others.

Examples of silica flow conditioners include colloidal silicon dioxide,magnesium aluminum silicate and guar gum.

Suitable surfactants include pharmaceutically acceptable non-ionic,ionic and anionic surfactants. An example of a surfactant is sodiumlauryl sulfate. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of nontoxic auxiliarysubstances such as wetting or emulsifying agents, pH-buffering agentsand the like, for example, sodium acetate, sorbitan monolaurate,triethanolamine sodium acetate, triethanolamine oleate, etc. If desired,flavoring, coloring and/or sweetening agents may be added as well.

Examples of stabilizing agents include acacia, albumin, polyvinylalcohol, alginic acid, bentonite, dicalcium phosphate,carboxymethylcellulose, hydroxypropylcellulose, colloidal silicondioxide, cyclodextrins, glyceryl monostearate, hydroxypropylmethylcellulose, magnesium trisilicate, magnesium aluminum silicate,propylene glycol, propylene glycol alginate, sodium alginate, carnaubawax, xanthan gum, starch, stearate(s), stearic acid, stearicmonoglyceride and stearyl alcohol.

Examples of thickening agent can be for example talc USP/EP, a naturalgum, such as guar gum or gum arabic, or a cellulose derivative such asmicrocrystalline cellulose NF/EP (e.g., Avicel™ PH 102),methylcellulose, ethylcellulose or hydroxyethylcellulose. A usefulthickening agent is hydroxypropyl methylcellulose (HPMC), an adjuvantwhich is available in various viscosity grades.

Examples of plasticizers include: acetylated monoglycerides; these canbe used as food additives; Alkyl citrates, used in food packagings,medical products, cosmetics and children toys; Triethyl citrate (TEC);Acetyl triethyl citrate (ATEC), higher boiling point and lowervolatility than TEC; Tributyl citrate (TBC); Acetyl tributyl citrate(ATBC), compatible with PVC and vinyl chloride copolymers; Trioctylcitrate (TOC), also used for gums and controlled release medicines;Acetyl trioctyl citrate (ATOC); Trihexyl citrate (THC), compatible withPVC, also used for controlled release medicines; Acetyl trihexyl citrate(ATHC), compatible with PVC; Butyryl trihexyl citrate (BTHC, trihexylo-butyryl citrate), compatible with PVC; Trimethyl citrate (TMC),compatible with PVC; alkyl sulphonic acid phenyl ester, polyethyleneglycol (PEG) or any combination thereof. Optionally, the plasticizer cancomprise triethyl citrate NF/EP.

Examples of permeation enhancers include: sulphoxides (such asdimethylsulphoxide, DMSO), azones (e.g., laurocapram), pyrrolidones (forexample 2-pyrrolidone, 2P), alcohols and alkanols (ethanol, or decanol),glycols (for example propylene glycol and polyethylene glycol),surfactants and terpenes.

In an embodiment, the pharmaceutical composition is an oral formulation,is for oral administration. In an embodiment, the pharmaceuticalcomposition is in the form of a tablet or pill.

Formulations suitable for oral administration may include (a) liquidsolutions, such as an effective amount of active agent(s)/composition(s)suspended in diluents, such as water, saline or PEG 400; (b) capsules,sachets or tablets, each containing a predetermined amount of the activeingredient, as liquids, solids, granules or gelatin; (c) suspensions inan appropriate liquid; and (d) suitable emulsions. Tablet forms caninclude one or more of lactose, sucrose, mannitol, sorbitol, calciumphosphates, corn starch, potato starch, microcrystalline cellulose,gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearicacid, and other excipients, colorants, fillers, binders, diluents,buffering agents, moistening agents, preservatives, flavoring agents,dyes, disintegrating agents, and pharmaceutically compatible carriers.Lozenge forms can comprise the active ingredient in a flavor, e.g.,sucrose, as well as pastilles comprising the active ingredient in aninert base, such as gelatin and glycerin or sucrose and acaciaemulsions, gels, and the like containing, in addition to the activeingredient, carriers known in the art.

Any suitable amount of the compound of formula I or pharmaceuticallyacceptable salt thereof, or pharmaceutical composition comprising same,may be administered to a subject. The dosages will depend on manyfactors including the mode of administration. Typically, the amount ofthe compound contained within a single dose will be an amount thateffectively prevent, delay or treat cancer (e.g., AML) without inducingsignificant toxicity.

For the prevention, treatment or reduction in the severity of cancer(e.g., AML), the appropriate dosage of the compound of formula I orpharmaceutically acceptable salt thereof or composition will depend, forexample, on the type of cancer to be treated, the severity and course ofthe cancer, whether the compound of formula I or pharmaceuticallyacceptable salt thereof, or composition, is administered for preventiveor therapeutic purposes, previous therapy, the patient's clinicalhistory and response to the compound of formula I or pharmaceuticallyacceptable salt thereof and the discretion of the attending physician.The compound of formula I or pharmaceutically acceptable salt thereof,or composition, may be suitably administered to the patient at one timeor over a series of treatments. Preferably, it is desirable to determinethe dose-response curve in vitro, and then in useful animal models,prior to testing in humans. The present disclosure provides dosages forthe compound of formula I or pharmaceutically acceptable salt thereof,and compositions comprising same. For example, depending on the type andseverity of the cancer (e.g., AML), about 1 μg/kg to about 1000 mg perkg (mg/kg) of body weight of the mitochondrial activity inhibitor may beadministered per day. In embodiments, the effective dose may be 0.5mg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg/25 mg/kg, 30mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 70mg/kg, 75 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg,175 mg/kg, 200 mg/kg, and may increase by 25 mg/kg increments up to 1000mg/kg, or may range between any two of the foregoing values. A typicaldaily dosage might range from about 1 μg/kg to 100 mg/kg or more,depending on the factors mentioned above. For repeated administrationsover several days or longer, depending on the condition, the treatmentis sustained until a desired suppression of disease symptoms occurs.However, other dosage regimens may be useful. The progress of thistherapy is easily monitored by conventional techniques and assays. Themitochondrial activity inhibitor, e.g., Mubritinib or pharmaceuticallyacceptable salt thereof, may be administered according to any suitabledosing schedule/regimen, e.g., twice-a-day, once-a-day, every 2 days,twice-a-week, weekly, etc. In an embodiment, the administration isonce-a-day.

In an embodiment, the pharmaceutical composition comprises from about0.1 mg to about 100 mg of the compound of formula I or pharmaceuticallyacceptable salt thereof. In further embodiments, the pharmaceuticalcomposition comprises from about 1 mg to about 50 mg, from about 2 mg toabout 30 mg, from about 5 mg to about 25 or 20 mg, or about 10 mg, ofthe compound of formula I or pharmaceutically acceptable salt thereof.

In an embodiment, the composition comprises the compound of formula I orpharmaceutically acceptable salt thereof and an additional active agent,e.g., a chemotherapeutic agent. The active agents arecombined/formulated in a single composition, and thus administered atthe same time for the methods/uses described above.

The recitation of an embodiment for a variable herein includes thatembodiment as any single embodiment or in combination with any otherembodiments or portions thereof. The recitation of an embodiment hereinincludes that embodiment as any single embodiment or in combination withany other embodiments or portions thereof.

Examples

The following non-limiting examples are illustrative embodiments andshould not be construed as further limiting the scope of the presentinvention. These examples will be better understood with reference tothe accompanying figures.

The Examples set forth herein below provide syntheses and experimentalresults obtained for certain exemplary compounds. Unless otherwiseindicated, all numbers expressing quantities of ingredients, reactionconditions, concentrations, properties, stabilities, and so forth usedin the specification and claims are to be understood as being modifiedin all instances by the term “about.” At the very least, each numericalparameter should at least be construed in light of the number ofreported significant digits and by applying ordinary roundingtechniques. Accordingly, unless indicated to the contrary, the numericalparameters set forth in the present specification and attached claimsare approximations that may vary depending upon the properties sought tobe obtained. Notwithstanding that the numerical ranges and parameterssetting forth the broad scope of the embodiments are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containcertain errors resulting from variations in experiments, testingmeasurements, statistical analyses and such.

Example 1: Materials and Methods

Human Leukemia Samples

This study was approved by the Research Ethics Boards (REB) ofUniversité de Montréal, Maisonneuve-Rosemont Hospital and CharlesLemoyne Hospital (Longueuil, QC, Canada). All AML samples were collectedwith an informed consent between 2001 and 2017 according to theprocedures of the Banque de Cellules Leucémiques du Québec (BCLQ).Umbilical cord blood (CB) units were collected from consenting mothersand human CD34⁺ CB cells were isolated with the EasySep® positiveselection kit (StemCell Technologies, Vancouver, Canada, catalog number18056) (Fares et al., Science. 2014 Sep. 19; 345(6203):1509-12).

Chemical Screen

Primary cells: frozen AML mono-nucleated cells were thawed at 37° C. inIscove's modified Dulbecco's medium (IMDM) containing 20% FBS and DNaseI (100 μg/mL). Cells were then cultured in optimized AML growth mediumas previously reported (Pabst, C. et al. Nature methods 11, 436-442,2014): IMDM, 15% BIT (bovine serum albumin, insulin, transferrin; StemCell Technologies®), 100 ng/mL SCF, 50 ng/mL FLT3-L, 20 ng/mL IL-3, 20ng/mL G-CSF (Shenandoah®), 10⁻⁴ M β-mercaptoethanol, 500 nM SR1(Alichem®), 500 nM UM729 (synthesized at the Medicinal Chemistry CoreFacility at the Institute for Research in Immunology and Cancer (IRIC)),gentamicin (50 μg/mL) and ciprofloxacin (10 μg/mL).

Expanded CB cells are cells that resulted from 6 days ofUM171-supplemented culture of fresh CB cells, as described in Fares etal., supra. Fresh CB cells are cells directly collected from umbilicalcord blood specimens, following a positive CD34 selection (EasySep® kit,StemCell Technologies, Vancouver, Canada), as described in Fares et al.,Science. 2014 Sep. 19; 345(6203):1509-12. CB cells (fresh and expanded)were cultivated in StemSpan®-ACF (Stemcell Technologies 09855)containing SCF 100 ng/mL, TPO 100 ng/mL, FLT3-L 50 ng/mL (Shenandoah®),Glutamax® 1X, LDL 10 μg/mL, ciprofloxacin 10 μg/mL, 500 nM SR1(Alichem®) and 35 nM UM171 (synthesized at the Medicinal Chemistry CoreFacility at the Institute for Research in Immunology and Cancer (IRIC)).

Cell lines. OCI-AML3 cells were maintained in alpha-MEM, 20% FBS whereasbreast tumor BT474 cells were maintained in DMEM 10% FBS. BT474 (ATCC®HTB-20™) was a kind gift from the laboratory of Sylvie Mader, whereasOCI-AML3 and OCI-AML5 cells were purchased from the German cell bank(DSMZ, accession Nos. ACC 582 and ACC 247, respectively).

Compounds. All powders were dissolved in DMSO and diluted in culturemedium immediately before use. Final DMSO concentration in allconditions was 0.1%. The 60 compounds were purchased from varioussuppliers including Santa Cruz, Selleckchem, Calbiochem, AdooQBioscience, Cayman chemical and Synkinase.

Cell dose-response viability assays. Patient cells were seeded in384-well plates at a density of 5,000 cells in 50 μL per well. In theinitial screen, compounds were added to seeded cells in serial dilutions(10 dilutions, 1:3, starting from 10 μM or 20 μM), in duplicates. Cellstreated with 0.1% DMSO without additional compound were used as negativecontrols. Viable cell counts per well were evaluated after 6 days ofculture using the CellTiterGlo® assay (Promega®) according to themanufacturer's instruction. The percent of inhibition was calculated asfollows: 100-(100×(mean luminescence(compound)/mean luminescence(DMSO));where mean-luminescence(compound) corresponds to the average ofluminescent signals obtained for the compound-treated cells, andmean-luminescence(DMSO) corresponds to the average of luminescentsignals obtained for the control DMSO-treated cells.

EC₅₀ values (corresponding to the concentration of compound required toreach 50% of inhibition) were calculated using ActivityBase® SARviewSuite (IDBS, London, UK) and GraphPad® Prism 4.03 (La Jolla, CA, USA) byfour-parameter-non-linear curve fitting methods.

Leukemic Stem Cell (LSC) Frequency Assessment.

LSC frequencies were assessed in immunocompromised NSG mice usinglimiting dilution assays, as detailed previously (Pabst, C. et al. Blood127, 2018-2027, 2016). NOD.Cg-Prkdc^(scid)II2^(tm1Wjl)/SzJ (NSG) micewere purchased from Jackson Laboratory® (Bar Harbor, Maine) and bred ina pathogen-free animal facility. All AML samples were transplanted viathe tail vein into 8 to 12-week old sublethally irradiated (250 cGy,¹³⁷Cs-gamma source) NSG mice. AML cells were transplanted at fourdifferent cell doses in groups of four recipient mice directly afterthawing. Human leukemic engraftment in mouse bone marrow was determinedby flow cytometry between 10 and 16 weeks post-transplant. On average150,000 gated events were acquired. Mice were considered positive ifhuman cells represented>1% of the bone marrow cell population. Mice wereexcluded only in case of obvious non-leukemia related death (e.g., firsttwo weeks after irradiation). To discriminate between engraftment ofleukemic and normal cells present in unsorted patient samples onlyrecipients with proportions of CD45⁺ CD33⁺ or CD45⁺ CD34⁺ cells higherthan proportions of CD19⁺CD33⁻ or CD3⁺ were considered to harbor cellsof leukemic origin.

Flow Cytometry Staining

The following FACS antibodies were used: anti-human CD45 Pacific Blue(BioLegend 304029), CD45 fluorescein isothiocyanate (FITC; BioLegend304006), CD33 phycoerythrin (PE; BD Bioscience 555450), CD33 BV421 (BD562854), CD34 antigen-presenting cell (APC; BD Bioscience 555824), CD34APC (Stem Cell Technologies 10613), CD3 FITC (BD Bioscience 555332), CD4APC-Cy7 (BD 560158), CD8 APC (BD 555369), CD3 PE-Cy5 (BD 555334), CD19PE-Cy7(BD Bioscience 557835), anti-mouse CD45.1 APC-efluor730(eBioscience 47-0453-82), ERBB2-PE (Biolegend®, 324406), Annexin V FITC(BD Bioscience®, 556419). Dead cells were stained using Propidium iodideat a final concentration of 1 μg/mL. For ROS quantification cells werestained with 1 μM H2DCFDA (Thermo Fisher, D399) under normal growthconditions. Cells were analyzed on LSRII® flow cytometer (BDBioscience®), BD Canto® cytometer (BD Bioscience) or on an IQue Screener(Intellicyt®) and results were analyzed with BD fluorescence-activatedcell sorter (FACS) Diva® 4.1 and FlowJo® X software.

Next-Generation Sequencing and Mutation Quantification

Workflow for sequencing, mutation analysis and transcriptsquantification have been described previously (Lavallée, V.-P. et al.Blood 125, 140-143, 2014; Lavallée, V.-P. et al. Nat. Genet. 47,1030-1037, 2015). Briefly, libraries were constructed with TruSeq®RNA/TruSeq® DNA Sample Preparation Kits (Illumina®). Sequencing wasperformed using an Illumina® HiSeq 2000 with 200 cycles paired end runs.Sequence data were mapped to the reference genome hg19 using theIllumina® Casava 1.8.2 package and Elandv2 mapping software according toRefSeq annotations (UCSC, Apr. 16^(th) 2014). Variants were identifiedusing Casava 1.8.2 and fusions or larger mutations such as partialtandem duplications with Tophat 2.0.7 and Cufflinks 2.1.1.

Transcript levels are given as Reads Per Kilobase per Million mappedreads (RPKM) and genes are annotated according to RefSeq annotations(UCSC, Apr. 16^(th) 2014).

LC/MS Metabolite Measurements (Citric Acid Cycle Intermediates andGlutathione)

LC/MS metabolite measurements were carried out at the McGillMetabolomics platform. Authentic metabolite standards were purchasedfrom Sigma-Aldrich Co., while the following LC/MS grade solvents andadditives were purchased from Fisher: ammonium acetate, formic acid,water, methanol, and acetonitrile. OCI-AML3 cells (5 million cells,quadruplicates, treated with either DMSO or Mubritinib 500 nM for 20 h)were washed twice with ice-cold 150 mM ammonium formate pH 7.2.Metabolites were then extracted using 380 μl of LC/MS grade 50%methanol/50% water mixture and 220 μl of cold acetonitrile. Samples werethen homogenized by 1.4 mm ceramic bead beating 2 min at 30 Hz(TissueLyser, Qiagen). A volume of 300 μl of ice-cold water and 600 μlof ice-cold methylene chloride were added to the lysates. Samples werevortexed and allowed to rest on ice for 10 min for phase separationfollowed by centrifugation at 4,000 rpm for 5 min. The upper aqueouslayer was transferred to a fresh pre-chilled tube. Samples wereeventually dried by vacuum centrifugation operating at −4° C. (Labconco)and stored at −80° C. until ready for LC-MS/MS data collection. ForLC-MS/MS analysis, specimens were first re-suspended in 50 μl of waterand clarified by centrifugation for 15 min at 15,000 rpm at 1° C.Samples were maintained at 4° C. for the duration of the LC-MS/MSanalysis in the autosampler. Specimens were separated by U-HPLC(Ultra-High-Performance Liquid Chromatography) (1290 Infinity, AgilentTechnologies) using a Scherzo SM-C18 (3 mm×150 mm) 3 μm column and guardcolumn (Imtakt USA) operating at 10° C.

Seahorse Metabolic Flux Experiments

Oxygen consumption rates and extracellular acidification rates weremeasured using a 96-well Seahorse Bioanalyzer XFe96® or XFe24® accordingto the manufacturer's instructions (Agilent Technologies). Seahorse XFBase medium was supplemented with 1 mM pyruvate, 2 mM glutamine and 10mM glucose in the case of Mitochondrial Stress Test and with 1 mMpyruvate, 2 mM glutamine and no glucose in the case of Glycolytic StressTest. The pH of the Seahorse media was then adjusted at 7.4 prior toassay. In brief, leukemic cells were seeded into Seahorse 96-well (or24-well) plates pre-coated for 3 h with poly-lysine (Sigma-Aldrich,P4707) at a density of 75,000 cells/well in 100 μL (or 150,000cells/well, in 150 μL) of temperature/CO₂ pre-adjusted Seahorse mediaper well. The Seahorse plates were then centrifuged at 1400 rpm for 5min. An additional 75 μL (or 375 μL) of Seahorse media was then addedand cells were eventually analyzed following the manufacturer'sinstructions by adding compounds in a constant volume of 25 μL (or 75μL). Compounds were acutely injected in cells at a final concentrationof 1 μM for Mubritinib, 1 μM for Oligomycin, 0.5 μM for FCCP, 0.5 μM forRotenone/Antimycin A, Glucose 10 mM and 2-Deoxy-Glucose 50 mM.

Cell-Free Assay for ETC Complex I Activity

The cell-free kit assay for ETC complex I activity was purchased fromMitoSciences (Abcam, Cambridge, UK), and used in accordance with themanufacturer's protocol. IC₅₀ values were calculated using GraphPad®Prism 4.03 (La Jolla, CA, USA) by four-parameter-non-linear curvefitting methods.

Statistics Analysis of differential gene expression was performed usingthe Wilcoxon rank-sum test and the false discovery rate (FDR) method wasapplied for global gene analysis as previously described (Lavallée,V.-P. et al. Blood 125, 140-143, 2014). Differential overall survivalp-values were calculated by log-rank test on patients belonging to theprognostic Leucegene cohort.

Example 2: HOX-High AML Patients Generally have a Poor Disease Prognosis

Consistent high expression of genes belonging to the HOX network (FIG.1A) in AML cell samples was shown to be associated with a significantlydecreased patient overall survival (FIG. 1B). FIG. 1C shows thecorrelation between HOXA9 and HOXA10 expression in leukemic cells, andFIG. 1D show that survival of AML patients belonging to the HOXA9/HOXA10high group is similar to that of patients belonging to HOX-network highsubgroup shown in FIG. 1B, indicating that high expression of HOXA9 andHOXA10 may be used as a surrogate for the detection of HOX network-highpatients. Overall, these data show that patients having AML cellsexhibiting high expression of HOX-network genes have a poor prognosisand would benefit from suitable AML treatments.

Example 3: Mubritinib Efficiently Inhibits HOX-High AML Cells

Using high expression of HOXA9 and HOXA10 as a surrogate for thedetection of HOX-network-high patient samples, the survival of HOX-highversus HOX-med/low specimens contacted with 60 inhibitors targetingreceptor tyrosine kinases (RTK), members of the RAS and P13K pathways,was assessed (FIG. 2A).

When compared to HOX-med/low samples, HOX-high patient cells weresignificantly more sensitive to the RTK ERBB2 inhibitor Mubritinib (FIG.2B). No statistically significant difference in sensitivity was observedfor the other compounds tested.

Dose response validation screening in a large cohort of AML samplesconfirmed that HOX-high patient cells are significantly more sensitiveto Mubritinib than HOX-med/low AML cells (FIGS. 2C-D). Median MubritinibEC₅₀ in the AML population tested was approximately 375 nM (FIG. 2E).Patients belonging to the Mubritinib-sensitive group (EC₅₀<375 nM) havea significantly decreased overall survival relative to patients of theMubritinib-resistant group (EC₅₀ 375 nM, FIG. 2F). Specimens belongingto the Mubritinib-sensitive group overexpress genes of the HOX network(FIG. 2G), consistent with the results presented in Example 2. The mostdifferentially expressed genes, (6-fold difference in RPKM values,RPKM>0.1) are shown in FIG. 2H and the complete Mubritinib sensitivitytranscriptomic signature in AML is displayed in Table 2b (genesoverexpressed more than 5-fold in RPKM values in Mubritinib-sensitivecells, RPKM>0.1), and Table 2a (genes under-expressed more than 5-foldin RPKM values in Mubritinib-sensitive cells, RPKM>0.1). Taken together,these data demonstrate that Mubritinib is a good candidate drug for thetreatment of AML patients, and particularly those with high expressionof HOX-network genes.

TABLE 2a Under-expressed genes* in Mubritinib- sensitive versusMubritinib-resistant Log(RPKM + Log(RPKM + FDR 0.0001)*100000.0001)*10000 Gene q-value resistant AML sensitive AML ORM1 0.0068 3.62.8 PRAME 0.0110 3.7 3.0 MYZAP 0.0019 3.0 2.3 SNORD116.4 0.0002 3.9 3.0SNORD116.24 0.0008 3.3 2.4 ZNF521 0.0031 4.5 3.6 MSLN 0.0001 3.9 2.6TINAGL1 0.0034 3.0 2.3 S100A16 0.0011 3.5 2.5 MS4A2 0.0003 3.8 3.0SNORD116.20 0.0003 3.4 2.4 KIRREL 0.0001 3.0 2.0 PRG3 0.0015 3.9 3.0ST18 0.0062 3.2 2.4 SNORD116.21 0.0016 3.4 2.5 *Mubritinib-sensitive (n= 100, separation by median of the entire cohort, EC₅₀ = 375 nM) versusMubritinib-resistant (n = 100) AML specimens according tofalse-discovery rate (FDR) corrected multiple Mann-Whitney test appliedto RNA-sequencing data. Cut-offs used: expression > 0.1 RPKM,log(fold-change) between sensitive and resistant specimens > 0.7(=5-fold difference in gene expression).

TABLE 2b Over-expressed genes* in Mubritinib- sensitive versusMubritinib-resistant Log(RPKM + Log(RPKM + FDR 0.0001)*100000.0001)*10000 Gene q-value resistant AML sensitive AML HOXA5 0.0065 4.25.0 HOXB5 0.0074 3.1 4.0 HOXB9 0.0078 2.3 3.2 HOXA4 0.0081 3.5 4.2 HOXA30.0088 3.6 4.4 HOXA9 0.0101 4.5 5.3 HOXA11 0.0206 2.5 3.3 HOXA10.AS0.0214 3.4 4.1 HOXA11.AS 0.0313 2.5 3.3 COL4A5 0.0006 2.8 4.0 PRDM160.0024 2.7 3.5 BEND6 0.0024 2.8 3.6 LINC00982 0.0025 2.1 3.1 NKX2.30.0002 2.4 3.9 ANKRD18B 0.0001 2.5 3.4 LOC285758 0.0009 3.8 4.5 MIR47400.0011 3.4 4.3 CYP7B1 0.0011 3.0 3.8 HOXA7 0.0043 3.6 4.5 HOXB.AS30.0004 2.7 4.1 HOXA.AS3 0.0051 2.9 3.9 HOXA6 0.0055 3.5 4.5*Mubritinib-sensitive (n = 100, separation by median of the entirecohort, EC₅₀ = 375 nM) versus Mubritinib-resistant (n = 100) AMLspecimens according to false-discovery rate (FDR) corrected multipleMann-Whitney test applied to RNA-sequencing data. Cut-offs used:expression > 0.1 RPKM, log(fold-change) between sensitive and resistantspecimens > 0.7 (=5-fold difference in gene expression).

Example 4: Mubritinib Target Population According to ClassicalGenetic/Cytogenetic Classifications

The results of a set of experiments aimed at identifying AML subtypesmore sensitive to Mubritinib are depicted in FIGS. 3A-F and Tables 3Aand 5A-5B. FIGS. 3A and 3E show that Mubritinib-sensitive AML cells mostfrequently belong to the intermediate cytogenetic risk class, oftencarry mutations in either NPM1, IDH1, SRSF2, CEBPA, DNMT3A or FLT3-ITD(FIGS. 3B, 3C and 3F), and generally have a normal karyotype (NK, Table3C and FIGS. 3D and 3E). The most significantly enriched mutated inMubritinib-sensitive versus resistant specimens were IDH1, SRSF2 andCEBPA, whereas AML samples mutations in NRAS, KIT, FLT3 not ITD and TP53were underrepresented in the Mubritinib-sensitive group relative to theMubritinib-resistant group (Table 3A). The detail of the mutations isdepicted in Table 3B.

TABLE 3A patient sample fold-enrichment in Mubritinib- sensitive versusMubritinib-resistant AML samples according to the presence of a mutatedgene. Genes Mubritinib Mubritinib Fold enrichment mutated sensitive (%)resistant (%) sensitive/resistant NPM1 36.6 22.4 1.6 FLT3-ITD 30.3 17.81.7 FLT3(not ITD) 8.5 15.0 0.6 DNMT3A 31.0 24.3 1.3 NRAS 10.6 22.4 0.5TET2 11.3 9.3 1.2 IDH2 9.2 7.5 1.2 KIT 0.7 16.8 0.0 TP53 3.5 5.6 0.6RUNX1 6.3 4.7 1.4 IDH1 8.5 2.8 3.0 WT1 5.6 4.7 1.2 SRSF2 6.3 1.9 3.4ASLX1 2.8 5.6 0.5 CEBPA 8.5 0.9 9.0

TABLE 3B Mutations present in the AML samples. Sample Mutations ASLX1R417*, A472−, G643−, G645−, L696−, Q708*, C759*, P763, L775*, E824−,E1006* CEBPA L219P, E215*, R204−, L196−, V195−, K194−, Q193−, Q312−,T191−, K304−, A184D, R300S, R178L, Y62*, H6Y, A113−, G96−, A91−, A79G,F77−, F73−, P70−, D69−, G38−, A30−, P23−, Y7* DNMT3A K906Q, G890S,L888M, R882H, R882P, R882C, F870−, W795R, S786L, R771*, W753R, F752L,P743S, R736C, F732C, F731Y, N717I, D712Y, G707D, I705T, Q692−, V684−,G673S, S669−, S669F, P625−, R597−, R597P, C586Y, L566*, G543C, Q527*,L508−, R379C, H355−, W330*, R326H, S304−, E30A FLT3-ITD 575−, A680V,D586−, D593−, D600−, D835H, D835V, D835Y, D839G, E573−, E596−, F590−,F594−, G583−, I836−, K602−, L789−, M578−, M837−, N587−, N676K, Q577−,Q580−, R595−, S451F, S574−, S584−, S585−, T582−, V581−, V592−, W603−,Y572−, Y589−, Y591−, Y597−, Y599− IDH1 R132C, R132G, R132H, R132S IDH2R172K, R140Q, R140L KIT D419−, D812V, D812Y, L416−, N818K, T417−, Y418−,Y418S NPM1 L258−, L287−, W259−, W261−, W288−, W290− NRAS G12A, G12C,G12D, G12S, G12V, G13C, G13D, G13R, Q61H, Q61K, Q61R, S17N, Y64D SRSF2P95H, P95L, P95R TET2 A1355T, A1379V, A1837−, A991−, C1271−, C1289S,C1298−, D1384N, D1587−, D688−, E692*, G1137V, G1275R, G1288C, G1430−,G1719−, G1869W, G563−, G613−, H1219D, L1457I, L1511−, M1456−, N1102−,N1103−, N1266S, N1774−, P1115−, P408−, P818−, Q1021−, Q1501*, Q383*,Q635*, Q705*, Q744*, Q810*, R1261C, R1516* S1050*, S1449−, S1838A,S217−, S675*, Y1598− TP53 A6P, C124−, E310−, G134R, K93−, L72Q, P190−,P322−, Q4*, R116Q, R141C, R141H, R150W, R26C, R273H, R81*, S83−, T86,V140M, V25F, V84−, V84G, V84M, Y102C, Y73C, Y88C WT1 A113−, H246−,H441−, P134−, P134Q, P266−, P376−, R369−, R370−, R380−, R458*, R462L,R462P, R462Q, S138−, S381−, S381*, S381X, T385−, V368−, V379−, *=mutation introducing a stop codon; −= frameshift mutation

ASXL1=NM_015338; CEBPA=NM_004364; DNMT3A=NM_022552; FLT3=NM_004119;IDH1=NM_005896; IDH2=NM_002168; KIT=NM_001093772; NPM1=NM_002520;NRAS=NM_002524; RUNX1=NM_001754; SRSF2=NM_003016; TET2=NM_017628;TP53=NM_001276760; WT1=NM_024426.

TABLE 3C Clinical features enriched in Mubritinib sensitive versusresistant AML specimens* Mubritinib Mubritinib sensitive resistantspecimens specimens (n = 100) (n = 100) P-value Age 58 (20-78) 56(17-75) n.s. WBC (×10⁹/L)   50 (1.6-361)   46 (1.5-447) n.s. Gender Male49 62 n.s. Female 51 38 n.s. Cytogenetic risk Favorable 4 33 n.s.Intermediate 80 43 5.6E−08 Adverse 15 24 n.s. Und 1 0 n.s. FAB M0 1 7n.s. M1 40 26 n.s. M2 16 11 n.s. M3 0 0 n.s. M4 11 9 n.s. M5 2 2 n.s. M60 0 n.s. M7 0 0 n.s. NC 12 15 n.s. Other 18 30 n.s. Genetic groupt(8:21) 1 11 n.s. inv(16) 3 22 n.s. Normal 59 25 8.9E−07 karyotypeIntermediate 17 11 n.s. abnormal K NUP98-NSD1 2 2 n.s. Trisomy/ 2 1 n.s.tetrasomy 8 MLL 7 12 n.s. Monosomy 5 1 1 n.s. Complex 7 12 n.s. EVI1 0 3n.s. Other 1 0 n.s. HOX status high 63 37 0.0002 low 37 63 n.s.*Mubritinib sensitive (EC₅₀ < 375 nM, n = 100) versus resistant (EC₅₀ ≥375 nM, n = 100) AML specimens according to a Bonferroni corrected exactFisher's test.

Notably, AML specimens with simultaneous mutations in NPM1, DNMT3A andFLT3-ITD, which was recently associated with a particularly adverseprognostic (Papaemmanuil, E. et al. N Engl J Med 374, 2209-2221, 2016),were shown to be particularly sensitive to Mubritinib (median EC₅₀ of 96nM as compared to 423 nM in other AMLs subtypes, FIG. 3F). Focusing onspecimens with a NK (representing 30% of AML patients, FIG. 3G) or onsamples with a NK and mutations in NPM1 (representing 25% of AML patientsamples, FIG. 3H), limiting dilution assays in immunocompromised micedemonstrate that Mubritinib-sensitive specimens have significantlyhigher frequencies of leukemic stem cells (LSCs) relative toMubritinib-resistant samples. High LSC frequency has been shown to begenerally associated with increased minimal residual disease (MRD) andpoor prognosis (see, e.g., Moshaver B. et al., Stem Cells 26, 3059-3067(2008)). Overall, these results provide useful indications for theselection of AML patient populations who might most benefit fromtreatment with Mubritinib, and provide evidence of a potential linkbetween sensitivity to Mubritinib and the frequency of LSCs in patientsamples.

Example 5: Assessment of the Mechanism of Action of Mubritinib in AML

Mubritinib treatment induces a reduction of live cell counts (asmeasured by a decrease in Propidium Iodide (PI)-negative cells) in adose-dependent manner (FIG. 4A). Cells are lost due to an increase inthe number of dead (PI-positive) cells (FIG. 4B), which appear to diethrough apoptosis, as suggested by the increase in Annexin V staining (amarker of apoptosis) in a Mubritinib-sensitive AML cell line, OCI-AML3.(FIG. 4C).

Mubritinib is described as a specific ERBB2 inhibitor (Nagasawa, J. etal. Int J Urol 13, 587-592, 2006), and it was next assessed whetherMubritinib acts through this target on AML cells. Another potent ERBB2inhibitor, Lapatinib, was included in the primary screen (FIG. 2A);strikingly, all 41 AML patient specimens tested were resistant toLapatinib, in contrast to Mubritinib (FIG. 4D). Similarly, OCI-AML3cells were sensitive to Mubritinib, but not to Lapatinib or Sapitinib,two other potent ERBB2 inhibitors (FIG. 4E), providing evidence thatMubritinib effects on AML cells is not shared by the class of ERBB2inhibitors. Overall, AML patient cells that were sensitive to Mubritinibhad the same low level of ERBB2 gene expression level asMubritinib-resistant specimens (median around 0.5 RPKM, FIG. 4F).Finally, flow cytometry analysis of ERBB2 expression have demonstratedthat the Mubritinib-sensitive AML cell line OCI-AML3 does not expressdetectable levels of ERBB2 protein, contrary to a positive controlbreast cancer cell line BT474 (FIG. 4G). Taken together, these resultsindicate that Mubritinib induces cell death in AML cells through atarget other than ERBB2.

It was next assessed whether apoptosis induced by Mubritinib treatmentinvolved oxidative stress, e.g., through the increase in reactive oxygenspecies (ROS). As shown in FIG. 5A, Mubritinib-induced apoptosis wassignificantly decreased when AML3 leukemic cells were incubated in thepresence of the ROS scavenger N-acetyl-cysteine (NAC). Also, the levelof ROS activity (hydroxyl, peroxyl), as assessed by the2′,7′-dichlorofluorescin diacetate (DCFDA) fluorogenic dye, wasincreased in AML3 cells treated with Mubritinib (FIG. 5B). Also, uponMubritinib treatment (500 nM, 24 h), the levels of oxidized glutathionewere increased (FIG. 5C), while the levels of reduced glutathione weredecreased (FIG. 5D), relative to DMSO control, in these leukemic cells,indicating that Mubritinib induces oxidative stress in sensitiveleukemic cells.

To assess whether Mubritinib-induced oxidative stress in sensitiveleukemic cells involves mitochondrial activity, namely the activity ofthe electron transfer chain (ETC), the oxygen consumption rate wasmeasured in cells treated with Mubritinib. As shown in FIG. 5E, acuteinjection of Mubritinib (1 μM) in OCI-AML3 leukemic cells impairedoxygen consumption rate in these cells. The data presented in FIG. 5Fdemonstrates that Mubritinib exhibits an inhibitory effect on ETCComplex I activity. FIG. 5G shows that the leukemic cell line OCI-AML5is resistant to Mubritinib-induced cell death, in contrast to OCI-AML3cells, which suggests that these cell lines exhibit metabolic ormitochondrial function disparities. Consistent with this hypothesis,OCI-AML3 were shown to be more sensitive than OCI-AML5 to othermitochondrial activity inhibitors such as Oligomycin (inhibitor of theF₁-F₀ ATP synthase, complex V, FIG. 5H), Rotenone (Class A inhibitor ofcomplex I, FIG. 5I) and Deguelin (Class A inhibitor of complex I, FIG.5J).

The results depicted in FIGS. 6A-6E show that Mubritinib treatmentreduces the levels of several intermediates of the citric acid cycle inOCI-AML3 cells, namely citrate (FIG. 6A), alpha-ketoglutarate (FIG. 6B),succinate (FIG. 6C), fumarate (FIG. 6D), and malate (FIG. 6E),confirming that Mubritinib impairs mitochondrial activity/respiration inthese leukemic cells. Mubritinib treatment was shown to inhibit pyruvatedehydrogenase (PDH) in an indirect fashion, and to induce a glycolyticswitch in OCI-AML3 cells.

The antidiabetic drug metformin has been shown to inhibit theproliferation of tumor cell lines (prostate, malignant melanoma andbreast), and to synergistically sensitize FLT3-ITD+AML cells to thekinase inhibitor sorafenib through enhancement of autophagy (Wang etal., 2015. Leukemia Research 39: 1421-1427). Metformin has also beenshown to inhibit mitochondrial complex I in HCT116 p53⁺ colon cancercells, but contrary to rotenone and antimycin, it does not increase ROS(H₂O₂) production by these cells (Wheaton et al., 2014. Elife.13(3):e02242). It was thus next tested whether there was a correlationbetween Mubritinib and metformin effect on AML cells. As shown in FIG. 7, comparison of the percentage of AML cell inhibition induced by eachcompound throughout the 20 AML specimens tested shows a lack ofcorrelation (Pearson correlation coefficient r=−0.17) betweenMubritinib's and Metformin's inhibitory effects in leukemic cells,providing evidence that these two compounds act through differentmechanisms of action and target different AML cells, and that Mubritinibactivity against AML cells involves induction of ROS production.

The inhibitory effect of Mubritinib on Complex I enzyme activity inOCI-AML3 cells was further assessed using the Complex I Enzyme ActivityMicroplate Assay Kit according to the manufacturer's instructions(Abcam, catalog No. ab109721). This assay measures the diaphorase-typeactivity of Complex I, which is not dependent on the presence ofubiquinone, and therefore inhibitors that bind at or near the ubiquinonebinding site, such as rotenone, do not inhibit this assay. The resultsdepicted in FIGS. 8A and B show that Mubritinib's inhibitory effect oncomplex I is NADH-independent (i.e. ubiquinone-dependent), as isdescribed for class A inhibitors such as rotenone (Fato et al., BiochimBiophys Acta, 2009 May; 1787(5): 384-392), consistent with Mubritinib'sability to increase ROS in these cells. FIG. 9 depicts the putativemechanism of action of Mubritinib for inducing tumor cell death.Mubritinib binds and inhibits Complex I in a ubiquinone-dependentmanner, leading to induction of ROS production and ROS-induced celldeath in sensitive cells.

In view of these results, heterocyclic compounds having structuralsimilarities with Mubritinib were synthesized and tested for the abilityto inhibit the growth of OCI-AML3 cells, which were shown to besensitive to ROS production induced by Mubritinib.

Example 6: Synthesis of Compounds Glossary

-   -   t-BuOH: tert-butyl alcohol    -   DCM: dichloromethane    -   DIPEA: diiopropyl ethylamine    -   DMF: dimethylformamide    -   DMSO: dimethylsulfoxide    -   EA: ethyl acetate    -   EDC: (3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride    -   HATU:        1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxid hexafluorophosphate    -   Hx: hexane    -   HOBT: Hydroxybenzotriazole    -   ISCO: Teledyne ISCO combiFlash chromatography system    -   Me-THF: 2-methyltetrahydrofuran    -   min: minute    -   rt: room temperature

Compound 1: Mubritinib, i.e.(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl-2-(4-trifluoromethyl)styryl)oxazole

Step 1: 4-(4-Methoxyphenyl)butyl methanesulfonate

Methanesulfonyl chloride (2.81 ml, 36.1 mmol) was added dropwise over 5minutes to a mixture of 4-(4-methoxyphenyl)butan-1-ol (5 g, 27.7 mmol)and triethylamine (5.22 ml, 37.4 mmol) in CH₂Cl₂ (75.0 ml, 1165 mmol) at0° C. Stirred at 0° C. for 10 minutes then slowly warmed to 20° C. After1 h, washed with water (50 mL), HCl 2% (60 mL) and NaHCO₃4% weight. (60mL). The organic layer was dried over MgSO₄, filtered and concentratedto dryness to give 7.32 g (102%) of the title compound.

Step 2: 1-(4-Azidobutyl)-4-methoxybezene

Method A: Sodium azide (2.346 g, 36.1 mmol) was added to a solution ofadded 4-(4-methoxyphenyl)butyl methanesulfonate (7.17 g, 27.8 mmol) inDMF and stirred overnight at rt. Then, it was heated to 40° C. for 48 h.The reaction mixture was cooled to 20° C. and quenched with water (10mL) and extracted with Et₂O (3×50 mL). The combined organic phases werewashed with water (50 mL) and then with brine (50 mL). The organic layerwas dried over MgSO₄, filtered and concentrated to give a tan oil. Theresidue was purified on ISCO using a RediSep® column (Hex/EtOAc) to give5.45 g of 1-(4-azidobutyl)-4-methoxybenzene.

Method B: Alternatively preparation: Diisopropyl azodicarboxy (DIAD)(13, 46 g, 66.6 mmol) was added dropwise to a cold solution oftriphenylphosphine (17, 46 g, 66.6 mmol) in THE (77 ml). After 20 min,4-(4-methoxyphenyl)butan-1-ol (9.60 ml, 55.5 mmol) in THE (77 ml) wasadded dropwise and stirred 40 min then diphenyl phosphorazidate (15.54ml, 72.1 mmol) was added dropwise. The mixture was brought to rt and letgo overnight. The reaction was concentrated under reduced pressure andthe crude compound was first purified with a pad of silica gel (eluent:Hex/EtOAc (95/5) then by ISCO using a RediSep® column (Hex/EtOAc(0-10%)) to give 5.36 g of the title compound.

Step 3: 1-(4-(4-Methoxyphenyl)butyl-1H-1,2,3-triazole

A mixture of 1-(4-azidobutyl)-4-methoxybenzene (3.0 g, 14.62 mmol) invinyl acetate (45.0 ml, 488 mmol) in a sealed tube was heated to 120° C.overnight. The solution was concentrated to dryness and the residuepurified on ISCO using a RediSep® column (DCM/EA) to give 3.38 g (92%)of the title compound. LRMS+H⁺=232.1.

Step 4: 4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenol

1-(4-(4-methoxyphenyl)butyl)-1H-1,2,3-triazole (3.38 g, 14.61 mmol) inHBr-water 48% wt. (9.57 ml, 85 mmol) was heated to 90° C. and stirredovernight. Sodium hydroxide 4M in water (38.3 ml, 153 mmol) was addeddropwise and the aqueous layer was washed with toluene (15 mL). Theaqueous layer was adjusted to pH 6.0-6.5 by addition of HCl 6M in water(7.79 ml, 46.8 mmol) and the mixture extracted with a mixture of EA(35.9 ml, 367 mmol) and THE (17.94 ml, 219 mmol). The organic layer waswashed with water (15 mL) and to the organic layer was added activatedcharcoal (270 mg). It was stirred for 15 minutes, filtered andconcentrated to dryness. Crystallization from ethyl acetate-hexane gave2.80 g (88%) of the title product.

Step 5:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl-2-(4-trifluoromethyl)styryl)oxazole

A mixture of (E)-4-(chloromethyl)-2-(4-(trifluoromethyl)styryl)oxazole(0.058 g, 0.203 mmol), prepared according to International patentpublication no. WO 01/77107, potassium carbonate (0.038 g, 0.276 mmol)and the previous phenol (0.040 g, 0.184 mmol) in DMF (0.368 ml) washeated at 80° C. for 5 h. It was cooled to rt and quenched with 1 mlwater-MeOH (3-1). The precipitate was filtered and purified on ISCOusing a RediSep® column (DCM/MeOH; 0-10%) to give 0.040 g (46%) of thetitle compound. LRMS+H⁺=469.1; (see WO 01/77107 A1)

Compound 2:(E)-4-((4-(1H-1,2,3-triazol-1-yl-)butyl)phenoxy)methyl)-2-(4-trifluoromethoxy)styryl)oxazole

Step 1:1-(4-(4-Methoxyphenyl)butyl)-4-(trimethylsilyl)-1H-1,2,3-triazole

To a solution of ethynyltrimethylsilane (0.700 g, 7.12 mmol) in DCM (5ml)-tBuOH (5 ml)-water (5 ml) was added1-(4-azidobutyl)-4-methoxybenzene (0.87 g, 4.24 mmol, step 2 of compound1, followed by CuSO₄·5H₂O (0.159 g, 0.636 mmol) and sodium ascorbate(0.378 g, 1.907 mmol). The mixture was stirred overnight, filtered andmost of the solvent removed. It was then extracted with in EA (2×),combined, dried over Na₂SO₄, filtered and the solvent removed.Purification on ISCO using a RediSep® column (Hx/EA; 0-80%) gave 0.22 g(17%) of the title compound.

Step 2: 4-(4-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)butyl)phenol

BBr₃ (2.17 ml, 2.17 mmol) was added dropwise to a −78° C. sol. of1-(4-(4-methoxyphenyl)butyl)-4-(trimethylsilyl)-1H-1,2,3-triazole (0.22g, 0.72 mmol) in DCM (5.0 ml). After 45 min at −78° C. the solution wasbrought to 0° C. and left overnight at the same temperature. Thereaction was quenched with 2 ml of MeOH and stirred with a saturatedsolution of NaHCO₃ for 1 h. It was diluted with DCM and the organicphase was separated, dried over Na₂SO₄, filtered and the solvent removedto give 0.175 g (83%) of crude material.

Step 3:(E)-4-((4-(1H-1,2,3-triazol-1-yl-)butyl)phenoxy)methyl)-2-(4-trifluoromethoxy)styryl)oxazole

NaH 60% (7.90 mg, 0.198 mmol) was added to a solution of4-(4-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)butyl)phenol (0.052 g,0.181 mmol) in THE (0.823 μml) at 0° C. After 10 μmin,(E)-4-(chloromethyl)-2-(4-(trifluoromethoxy)styryl)oxazole (0.050 g,0.165 mmol) was added and heated overnight at 80° C. The mixture wasquenched with a NH₄Cl solution and extracted 2× with EA. The combinedorganic solution was dried over Na₂SO₄, filtered and purified onpreparative HPLC (water-MeOH, 5% HCO₂H; 35%-100%) to give 0.024 g (30%)of the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.61-1.67 (m, 2H)1.89-2.00 (m, 2H) 2.58-2.65 (m, 2H) 4.40 (t, J=7.04 Hz, 2H) 5.02 (d,J=0.78 Hz, 2H) 6.88-6.95 (m, 3H) 7.08 (d, J=8.61 Hz, 2H) 7.25 (d, J=9.00Hz, 2H) 7.49-7.59 (m, 4H) 7.69 (d, J=13.69 Hz, 2H). LRMS+H⁺: 485.2.

Compounds 3A and 3B:(E)-2-(4-Bromo-2-fluorostyryl)-4-((4-(4-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazoleand (E)-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-bromo-2-fluorostyryl)oxazole

Step 1: (E)-3-(4-bromo-2-fluorophenyl)acrylamide

Oxalyl chloride (0.429 ml, 4.90 mmol) was added to a suspension of(E)-3-(4-bromo-2-fluorophenyl)acrylic acid (1 g, 4.08 mmol) in DCM (27.2ml) at 0° C. and DMF (8.74 μl, 0.122 mmol) was added. Bring to rt andlet go 2 h. The solvent removed, the residue taken in EA and the solventremoved. It was taken in EA and NH₄OH conc. (6.15 ml, 86 mmol) was addedslowly. It was stirred 30 minutes and diluted with EA. The organic phasewas separated and washed with brine, dried over Na₂SO₄, filtered and thesolvent removed to give 0.88 g of the title compound. ¹H NMR (400 MHz,CCCl₃) δ ppm 5.60 (br. s., 2H) 6.59 (d, J=16.04 Hz, 1H) 7.28-7.34 (m,2H) 7.35-7.42 (m, 1H) 7.66 (d, J=16.04 Hz, 1H).

Step 2: (E)-2-(4-Bromo-2-fluorostyryl)-4-(chloromethyl)oxazole

A mixture of (E)-3-(4-bromo-2-fluorophenyl)acrylamide (0.876 g, 3.59mmol) and 1,3-dichloropropan-2-one (0.911 g, 7.18 mmol) in toluene (7.18ml) was heated to reflux with a Dean-Stark for 24 h. The solvent wasremoved, and the residue absorbed on SiO₂ with DCM. Purification on ISCOusing a RediSep® column (Hx-EA; 0-40%) gave 0.61 g of the titlecompound. LRMS+H⁺: 315.9.

Step 3:(E)-2-(4-Bromo-2-fluorostyryl)-4-((4-(4-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazoleand(E)-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-bromo-2-fluorostyryl)oxazole

NaH 60% (6.89 mg, 0.172 mmol) was added to a solution of adduct fromcompound 2 step 2 (0.042 g, 0.144 mmol) in DMF (0.718 ml). Then at 0° C.was added the previous oxazole (0.050 g, 0.158 mmol). Bring to rt for 3h later it was quenched with a NH4Cl solution. Extracted 2× with EA,dried with Na2SO4, filtered and purified on ISCO using a RediSep® column(Hx-EA; 0-100%) to give 0.010 g of(E)-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-bromo-2-fluorostyryl)oxazole3A. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.61-1.67 (m, 2H) 1.89-2.00 (m, 2H)2.58-2.65 (m, 2H) 4.40 (t, J=7.04 Hz, 2H) 5.02 (d, J=0.78 Hz, 2H)6.88-6.95 (m, 3H) 7.08 (d, J=8.61 Hz, 2H) 7.25 (d, J=9.00 Hz, 2H)7.49-7.59 (m, 4H) 7.69 (d, J=13.69 Hz, 2H). HRMS+H⁺: 499.0946.

The second adduct needed more purification on preparative HPLC(water-MeOH, 5% HCO₂H, 35%-100%) to give 0.036 g of(E)-2-(4-Bromo-2-fluorostyryl)-4-((4-(4-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazole3B. ¹H NMR (400 MHz, CDCl₃) δ 0.31 (s, 9H) 1.58-1.70 (m, 2H) 1.85-1.98(m, 2H) 2.60 (t, J=7.63 Hz, 2H) 4.37 (t, J=7.24 Hz, 2H) 5.01 (s, 2H)6.91 (d, J=8.61 Hz, 2H) 7.05-7.10 (m, 3H) 7.28-7.34 (m, 2H) 7.41 (d,J=7.83 Hz, 1H) 7.45 (s, 1H) 7.57 (d, J=16.82 Hz, 1H) 7.67 (s, 1H).HRMS+H⁺: 571.1344.

Compound 4:(E)-2-(1-(4-(4-((2-(4-Trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl-1H-1,2,3-triazol-4-yl)ethanol

Step 1:(E)-4-(4-((2-(4-Trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butan-1-ol

A mixture of (E)-4-(chloromethyl)-2-(4-(trifluoromethyl)styryl)oxazole(0.249 g, 0.866 mmol), 4-(4-hydroxybutyl)phenol (0.12 g, 0.722 mmol),K₂CO₃ (0.120 g, 0.866 mmol) and Nal (0.108 g, 0.722 mmol) in acetone(3.61 ml) was heated at reflux for 6 h. The reaction was diluted with EAand water. The organic phase was separated and the aqueous was extractedwith EA and combined with the previous one. It was then dried on Na₂SO₄,filtered and the solvent removed. Purification on ISCO using a RediSep®column (Tol-EA; 0-100%) gave 0.115 g of the title compound. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.33-1.47 (m, 2H) 1.49-1.62 (m, 2H) 3.39 (q, J=6.26Hz, 2H) 4.34 (t, J=5.28 Hz, 1H) 4.99 (s, 2H) 6.90-6.97 (m, 2H) 7.11 (m,J=8.61 Hz, 2H) 7.34 (d, J=16.82 Hz, 1H) 7.62 (d, J=16.43 Hz, 1H) 7.76(m, J=8.22 Hz, 2H) 7.95 (m, J=8.22 Hz, 2H), 8.24 (s, 1H).

Step 2:(E)-4((4-(4-azidobutyl)phenoxy)methyl)-2-(4-(trifluoromethyl)styryl)oxazole

This compound was prepared in a similar fashion as compound 1 step 2(method B). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.58-1.75 (m, 4H) 2.61 (t,J=7.24 Hz, 2H) 3.29 (t, J=6.65 Hz, 2H) 5.04 (d, J=0.78 Hz, 2H) 6.90-6.97(m, 2H) 7.03 (d, J=16.43 Hz, 1H) 7.12 (m, J=8.61 Hz, 2H) 7.56 (d,J=16.43 Hz, 1H) 7.61-7.68 (m, 4H) 7.69 (s, 1H).

Step 3:(E)-2-(1-(4-(4-((2-(4-Trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl-1H-1,2,3-triazol-4-yl)ethano

CuSO₄.5H₂O (2.1 mg, 8.4 μmol) and but-3-yn-1-ol (3.9 mg, 0.05 mmol) inTHE (0.28 ml) and triethylamine (9.4 μl, 0.06 mmol) were stirred for 15min then, the previous azido analogue (0.025 g, 0.057 mmol) was addedand the reaction was stirred overnight. SiO₂ was added and the solventremoved. Purification on ISCO using a RediSep® column (Hx-EA; 0-100%)gave 0.012 g of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm1.42-1.55 (m, 2H) 1.71-1.84 (m, 2H) 2.51-2.57 (m, 2H) 2.74 (t, J=7.04Hz, 2H) 3.61 (q, J=5.80 Hz, 2H) 4.31 (t, J=7.04 Hz, 2H) 4.67 (t, J=5.28Hz, 1H) 4.98 (s, 2H) 6.94 (m, J=8.61 Hz, 2H) 7.10 (m, J=8.22 Hz, 2H)7.34 (d, J=16.43 Hz, 1H) 7.62 (d, J=16.43 Hz, 1H) 7.76 (m, J=8.22 Hz,2H) 7.83 (s, 1H) 7.95 (m, J=8.22 Hz, 2H) 8.24 (s, 1H). HRMS+H⁺:513.2129.

Compound 5:(E)-4-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl-methoxy)phenyl)butyl-1H-1,2,3-triazol-4-yl)butan-1-al

This compound was prepared in a similar fashion as compound 4 withhex-5-yn-1-ol. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46 (quin, J=7.60 Hz,2H) 1.72-1.82 (m, 2H) 3.97 (s, 2H) 4.31 (t, J=7.04 Hz, 2H) 4.98 (s, 2H)6.93 (m, 2H) 7.07 (m, 2H) 7.15-7.31 (m, 5H) 7.34 (d, J=16.43 Hz, 1H)7.62 (d, J=16.43 Hz, 1H) 7.76 (m, 2H) 7.82 (s, 1H) 7.95 (m, 2H) 8.24 (s,1H). LRMS+H⁺: 541.2.

Compound 6: (E)-diethyl1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazole-4,5-dicarboxylate

(E)-4((4-(4-azidobutyl)phenoxy)methyl)-2-(4-(trifluoromethyl)styryl)oxazole(0.025 g, 0.057 mmol) and diethyl but-2-ynedioate (0.019 g, 0.113 mmol)in toluene (0.283 ml) were heated to 105° C. overnight. Purification onpreparative HPLC (water-MeOH, 5% HCOOH; 35%-100%) gave 0.015 g of thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21-1.31 (m, 6H) 1.51(quin, J=7.40 Hz, 2H) 1.83 (quin, J=7.24 Hz, 2H) 2.52-2.58 (m, 2H)4.26-4.40 (m, 4H) 4.56 (t, J=7.04 Hz, 2H) 4.98 (s, 2H) 6.94 (d, J=8.61Hz, 1H) 7.09 (d, J=8.61 Hz, 1H) 7.34 (d, J=16.43 Hz, 1H) 7.61 (d,J=16.43 Hz, 1H) 7.76 (d, J=8.22 Hz, 2H) 7.95 (d, J=8.22 Hz, 2H) 8.23 (s,1H). LRMS+H⁺: 613.2.

Compound 7:(E)-N-methyl-1-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)methanamine

To a solution of N-methylprop-2-yn-1-amine (0.016 g, 0.226 mmol) in DCM(0.251 ml), tBuOH (0.251 ml) and water (0.251 ml) was added(E)-4-((4-(4-azidobutyl)phenoxy)methyl)-2-(4-(trifluoromethyl)styryl)oxazole(0.050 g, 0.113 mmol) followed by CuSO₄.5H₂O (0.021 g, 0.085 mmol) andby sodium ascorbate (0.034 g, 0.170 mmol). It was stirred overnight,diluted with 2-methyltetrahydrofuran and heated to get a solution. Thiswas quenched with a NH₄Cl solution and the organic phase was separatedand extracted with 2-methyltetrahydrofuran. The combined organic phaseswere dried over Na₂SO₄, filtered and purified on ISCO using a RediSep®column DCM-MeOH—NH₄OH (77.5-22-2.5%) to give 0.016 g of the titlecompound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.63 (m, 4H) 2.51-2.56(m, 2H) 2.72 (t, J=7.04 Hz, 2H) 4.99 (s, 2H) 6.95 (d, J=8.61 Hz, 2H)7.13 (d, J=8.61 Hz, 2H) 7.34 (d, J=16.43 Hz, 1H) 7.61 (d, J=16.82 Hz,1H) 7.76 (d, J=8.61 Hz, 2H) 7.95 (d, J=8.22 Hz, 2H) 8.24 (s, 1H) 8.43(br. s., 1H). LRMS+H⁺: 512.2.

Compound 8:(E)-1-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)cyclopentanol

To a solution of 1-ethynylcyclopentanol (0.025 g, 0.226 mmol) in DCM(0.251 ml)-tBuOH (0.251 ml)-water (0.251 ml) was added first(E)-4-((4-(4-azidobutyl)phenoxy)methyl)-2-(4-(trifluoromethyl)styryl)oxazole(0.050 g, 0.113 mmol) followed by CuSO₄.5H₂O (0.021 g, 0.085 mmol) andsodium ascorbate (0.034 g, 0.170 mmol). This was stirred overnight. Itwas taken in 2-methyltetrahydrofuran and heated to get a solution andquenched with a NH₄Cl solution. Separated and extracted with Me-THF.Combined, Na₂SO4 dried and the solvent removed. It was absorbed on SiO₂and purified on ISCO using a RediSep® column Hx-EA (30-100%) to give 40mg of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51 (quin,J=7.60 Hz, 2H) 1.61-1.71 (m, 2H) 1.74-1.86 (m, 6H) 1.89-2.00 (m, 2H)2.54 (t, J=7.63 Hz, 2H) 4.32 (t, J=7.04 Hz, 2H) 4.93 (s, 1H) 4.99 (s,2H) 6.94 (d, J=8.61 Hz, 2H) 7.10 (d, J=8.61 Hz, 2H) 7.34 (d, J=16.43 Hz,1H) 7.62 (d, J=16.43 Hz, 1H) 7.76 (d, J=8.22 Hz, 2H) 7.85 (s, 1H) 7.95(d, J=8.22 Hz, 2H) 8.24 (s, 1H). LRMS+H⁺: 553.2.

Compound 9:(E)-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazole-4,5-diyl)dimethanol

A mixture of(E)-4((4-(4-azidobutyl)phenoxy)methyl)-2-(4-(trifluoromethyl)styryl)oxazole(0.030 g, 0.068 mmol) and but-2-yne-1,4-diol (0.025 ml, 0.339 mmol) wereheated to 90° C. 8 h. The crude was purified on ISCO using a RediSep®column (DCM-MeOH; 0-10%%) to give 0.016 g of the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.55 (quin, J=7.80 Hz, 2H) 1.83 (quin, J=7.20Hz, 1H) 2.55 (t, J=7.43 Hz, 2H) 4.34 (t, J=7.24 Hz, 2H) 4.49 (d, J=5.48Hz, 2H) 4.58 (d, J=5.48 Hz, 2H) 4.95-5.03 (m, 3H) 5.31 (t, J=5.48 Hz,1H) 6.94 (m, J=8.61 Hz, 2H) 7.11 (m, J=8.61 Hz, 2H) 7.34 (d, J=16.43 Hz,1H) 7.62 (d, J=16.43 Hz, 1H) 7.76 (m, J=8.22 Hz, 2H) 7.95 (m, J=8.22 Hz,2H) 8.24 (s, 1H). LRMS+H⁺: 529.2.

Compound 10:(E)-4-((1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)methyl)thiomorpholine1,1-dioxide

This compound was prepared in a similar fashion as compound 7 with4-(prop-2-yn-1-yl)thiomorpholine 1,1-dioxide. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.48 (quin, J=7.53 Hz, 2H) 1.80 (quin, J=7.34 Hz, 2H) 2.52-2.57(m, 2H) 2.83-2.90 (m, 4H) 3.05-3.12 (m, 4H) 3.75 (s, 2H) 4.35 (t, J=7.04Hz, 2H) 4.98 (s, 2H) 6.94 (d, J=9.00 Hz, 2H) 7.09 (d, J=8.61 Hz, 2H)7.34 (d, J=16.43 Hz, 1H) 7.62 (d, J=16.43 Hz, 1H) 7.76 (d, J=8.22 Hz,2H) 7.95 (d, J=8.22 Hz, 2H) 8.01 (s, 1H) 8.23 (s, 1H). LRMS+H⁺: 616.1.

Compound 11:4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)phenethyl)oxazole

A suspension of compound 48 (31 mg, 0.064 mmol) and Pd—C 10%, Degussatype, 50% wet (5.43 mg, 2.55 μmol) in EA (2 ml) was stirred under ahydrogen atmosphere for 1.5 h. The mixture was filtered and reloadedwith more Pd—C 10%, Degussa type, 50% wet (5.43 mg, 2.55 μmol), EA (2ml) and MeOH (2 ml) and stirred under a hydrogen atmosphere for 5 h. Themixture was filtered on a 45 μm syringe filter, washed with MeOH (1 ml)then EA (2 ml) and concentrated to afford the title compound. ¹H NMR(500 MHz, CCCl₃) δ ppm 1.59-1.67 (m, 2H) 1.94 (dt, J=14.98, 7.33 Hz, 2H)2.61 (t, J=7.57 Hz, 2H) 3.06-3.15 (m, 2H) 3.16-3.24 (m, 2H) 4.40 (t,J=7.25 Hz, 2H) 4.95 (d, J=0.95 Hz, 2H) 6.86-6.92 (m, 2H) 7.03-7.09 (m,2H) 7.28-7.35 (m, 3H) 7.50 (s, 1H) 7.59 (s, 1H) 7.70 (s, 1H). LRMS+H⁺:489.3.

Compound 12:(E)-N-(prop-2-yn-1-yl)-5-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)pentanamide

Step 1:(E)-5-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)pentanoicacid

To(E)-4((4-(4-azidobutyl)phenoxy)methyl)-2-(4-(trifluoromethyl)styryl)oxazole(0.150 g, 0.339 mmol) and hept-6-ynoic acid (0.064 g, 0.509 mmol) intBuOH (2.5 ml)-DCM (2.500 ml)-water (2.500 ml) was added firstcopper(II) sulfate pentahydrate (0.063 g, 0.254 mmol) followed by sodiumascorbate (0.101 g, 0.509 mmol). After 1 h, it was diluted with EA-waterand filtered on celite. The organic phase was separated and the aqueousextracted with EA. The organic phases were combined, Na₂SO₄ dried,filtered and the solvent removed. The crude residue was absorbed on SiO₂and purified on a short pad of SiO₂ with 100% EA followed by 5% MeOH inEA to give 0.146 g of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.43-1.63 (m, 6H) 1.72-1.84 (m, 2H) 2.23 (t, J=6.85 Hz, 2H)2.52-2.56 (m, 2H) 2.59 (t, J=7.24 Hz, 2H) 4.30 (t, J=7.04 Hz, 2H) 4.98(s, 2H) 6.94 (d, J=8.61 Hz, 2H) 7.09 (d, J=8.61 Hz, 2H) 7.34 (d, J=16.43Hz, 1H) 7.62 (d, J=16.43 Hz, 1H)_(7.76) (d, J=8.22 Hz, 2H) 7.82 (s, 1H)7.95 (d, J=7.83 Hz, 2H) 8.24 (s, 1H) 11.99 (br. s., 1H).

Step 2:(E)-N-(prop-2-yn-1-yl)-5-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)pentanamide

HATU (0.067 μg, 0.176 μmmol) was added to(E)-5-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)pentanoicacid (0.080 g, 0.141 mmol) in DMF (1.0 ml). After 10 min Hunig's Base(0.074 ml, 0.422 mmol) was added followed by prop-2-yn-1-amine (9.69 mg,0.176 mmol) and let go overnight. It was then diluted with EA-NaHCO₃solution and the organic phase separated and the aqueous phase extractedwith EA. The combined phases were dried over Na₂SO₄, filtered andabsorbed on SiO₂ to purify on ISCO using a RediSep® column usingDCM-MeOH—NH₄OH (77.5-20-2.5) to give 0.056 g of the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.43-1.59 (m, 6H) 1.78 (quin, J=7.40 Hz,2H) 2.10 (t, J=6.85 Hz, 2H) 2.52-2.55 (m, 2H) 2.58 (t, J=6.85 Hz, 2H)3.07 (t, J=2.35 Hz, 1H) 3.83 (dd, J=5.28, 2.54 Hz, 2H) 4.30 (t, J=7.04Hz, 2H) 4.98 (s, 2H) 6.94 (d, J=8.61 Hz, 2H) 7.09 (d, J=8.61 Hz, 2H)7.34 (d, J=16.82 Hz, 1H) 7.62 (d, J=16.43 Hz, 1H) 7.76 (d, J=8.22 Hz,2H) 7.81 (s, 1H) 7.95 (d, J=8.22 Hz, 2H) 8.19-8.29 (m, 2H). LRMS+H⁺:606.6.

Compound 13:(E)-2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethanamine

This compound was prepared in a similar fashion as compound 7 withbut-3-yn-1-amine. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.49 (dt, J=15.06,7.73 Hz, 2H) 1.78 (quin, J=7.34 Hz, 2H) 2.52-2.56 (m, 2H) 2.66 (br. s.,2H) 2.78 (br.s., 2H) 4.31 (t, J=7.04 Hz, 2H) 4.98 (s, 2H) 6.94 (d,J=8.61 Hz, 2H) 7.10 (d, J=8.61 Hz, 2H) 7.34 (d, J=16.43 Hz, 1H) 7.62 (d,J=16.43 Hz, 1H) 7.76 (d, J=8.22 Hz, 2H) 7.84 (s, 1H) 7.95 (d, J=8.22 Hz,2H) 8.24 (s, 1H). HRMS+H⁺: 512.2280.

Compound 14:(E)-N-(2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethyl)pent-4-ynamide

This compound was prepared in a similar fashion as compound 12 step 2with pent-4-ynoic acid and compound 13. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.49 (quin, J=7.20 Hz, 2H) 1.78 (quin, J=7.40 Hz, 2H) 2.20-2.27 (m, 2H)2.30-2.37 (m, 2H) 2.52-2.58 (m, 2H) 2.69-2.78 (m, 3H) 3.25-3.31 (m, 2H)4.31 (t, J=7.04 Hz, 2H) 4.98 (s, 2H) 6.94 (d, J=8.61 Hz, 2H) 7.10 (d,J=8.22 Hz, 2H) 7.34 (d, J=16.43 Hz, 1H) 7.62 (d, J=16.43 Hz, 1H) 7.76(d, J=8.22 Hz, 2H) 7.85 (s, 1H) 7.91-8.02 (m, 3H) 8.24 (s, 1H). LRMS+H⁺:592.2.

Compound 15:(E)-4-((1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-5-yl)methyl)thiomorpholine1,1-dioxide

Step 1:4-((1-(4-(4-methoxyphenyl)butyl)-1H-1,2,3-triazol-5-yl)methyl)thiomorpholine1,1-dioxide

Chloro(pentamethylcyclopentadienyl)ruthenium(II) tetramer (0.039 g,0.036 mmol) was added to a degassed solution of intermediate of step 2compound 1 and 4-(prop-2-yn-1-yl)thiomorpholine 1,1-dioxide (0.169 g,0.974 mmol) in DMF (6.50 ml) at rt. After 1 h the mixture was dilutedwith EA-water. The organic phase was separated and the aqueous extractedwith EA. They were then combined, Na₂SO₄ dried, filtered and the solventremoved. It was absorbed on SiO₂ and purified on ISCO using a RediSep®column (DCM-MeOH—NH₄OH; 77.5-20-2.5) to give 0.160 g of a 1:1 mixture ofthe title compound with the starting alkyne.

Step 2:4-((1-(4-(4-hydroxyphenyl)butyl)-1H-1,2,3-triazol-5-yl)methyl)thiomorpholine1,1-dioxide

A mixture of the previous mixture in HBr (48% in water; 2.5 ml) washeated at 95° C. for 3.5 h. It was then diluted with toluene and thesolvents were removed. The residue was taken in DCM and quenched with aNaHCO₃ solution. The organic phase was separated and the aqueousextracted with DCM. They were combined, Na₂SO₄, dried, filtered and thesolvent removed. It was then absorbed on SiO2 and purified on ISCO usinga RediSep® column (DCM/MeOH; 0-10%) to give 0.036 g of the titlecompound.

Step 3:(E)-4-((1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-5-yl)methyl)thiomorpholine1,1-dioxide

This compound was prepared in a similar fashion as compound 1 step 5with the previous phenol and(E)-4-(chloromethyl)-2-(4-(trifluoromethyl)styryl)oxazole. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.55 (quin, J=7.30 Hz, 2H) 1.80 (quin, J=7.34 Hz,2H) 2.55 (t, J=7.63 Hz, 2H) 2.86 (br. s., 4H) 3.02-3.11 (m, 4H) 3.77 (s,2H) 4.35 (t, J=7.24 Hz, 2H) 4.99 (s, 2H) 6.94 (d, J=8.61 Hz, 2H) 7.11(d, J=8.61 Hz, 2H) 7.34 (d, J=16.43 Hz, 1H) 7.57-7.66 (d, 2H) 7.76 (d,J=8.22 Hz, 2H) 7.95 (d, J=8.22 Hz, 2H) 8.23 (s, 1H). LRMS+H⁺: 616.1.

Compound 16:(E)-4-(1H-1,2,3-triazol-1-yl)-1-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butan-1-one

Step 1: 1-(4-methoxyphenyl)-4-(1H-1,2,3-triazol-1-yl)butan-1-one

4-azido-1-(4-methoxyphenyl)butan-1-one (1.32 g, 6.02 mmol), preparedfrom International Patent Publication no. WO 2006/032453 in vinylacetate (100 ml) was heated in the microwave for 14 h at 120° C. inthree separate experiment and combined at the end of the experiments.The solvent was removed and the crude purified on ISCO using a RediSep®column (Hx-EA; 25-100%) to give 1.22 g of the title compound.

Step 2: 1-(4-hydroxyphenyl)-4-(1H-1,2,3-triazol-1-yl)butan-1-one

A mixture of the previous ketone (0.500 g, 2.039 mmol) in HBr 48% inwater (5.0 ml, 92 mmol) was heated at 90° C. for 24 h. The solvent wasremoved and the residue diluted with EA. The solution was neutralizedwith a NaHCO₃ solution and acidified with a tartaric acid solution. Theorganic phase was separated and the aqueous was extracted 3 times withEA. The organic phases were combined, Na₂SO₄ dried, filtered and thesolvent removed to give 0.25 g of the crude title compound.

Step 3:(E)-4-(1H-1,2,3-triazol-1-yl)-1-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butan-1-one

This compound was prepared in a similar fashion as compound 1 step 5with the previous phenol and(E)-4-(chloromethyl)-2-(4-(trifluoromethyl)styryl)oxazole. ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.15 (quin, J=7.00 Hz, 2H) 3.00 (t, J=7.04 Hz, 2H)4.45 (t, J=7.04 Hz, 2H) 7.16 (d, J=8.61 Hz, 2H) 7.34 (d, J=16.43 Hz, 1H)7.63 (d, J=16.82 Hz, 1H) 7.73 (s, 1H) 7.76 (d, J=8.22 Hz, 2H) 7.87-7.99(m, 4H) 8.17 (s, 1H) 8.30 (s, 1H). LRMS+H⁺:483.3.

Compound 17:(E)-4-(1H-1,2,3-triazol-1-yl)-1-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butan-1-ol

The previous ketone (0.013 g, 0.027 mmol) in MeOH (1.5 ml) was heated inthe microwave for 4 minutes at 140° C. to get the product in solution.Then at rt, NaBH₄ (0.005 mg, 0.132 μmol) was added. The mixture wasquenched with HOAc and the solvent removed. Purification on ISCO using aRediSep® column (Hx-EA; 80-100%) gave 0.0044 g of the title compound. —HNMR (400 MHz, DMSO-d₆) δ ppm 1.42-1.60 (m, 2H) 1.68-1.82 (m, 1H)1.82-1.95 (m, 1H) 4.37 (t, J=7.04 Hz, 2H) 4.45-4.54 (m, 1H) 5.00 (s, 2H)5.14 (d, J=4.70 Hz, 1H) 6.97 (d, J=9.00 Hz, 2H) 7.21 (d, J=8.61 Hz, 2H)7.34 (d, J=16.43 Hz, 1H) 7.62 (d, J=16.83 Hz, 1H) 7.70 (s, 1H) 7.76 (d,J=8.22 Hz, 2H) 7.95 (d, J=8.22 Hz, 2H) 8.09 (s, 1H) 8.24 (s, 1H).HRMS+H⁺: 485.1774.

Compound 18:(E)-4-(1H-1,2,3-triazol-1-yl)-1-(4-((2-(4-(trifluoromethoxy)styryl)oxazol-4-yl)methoxy)phenyl)butan-1-one

This compound was synthesized as described in Example 1 (page 20) ofInternational Patent Publication no. WO 2006/032453.

Compound 19:(E)-4-(1H-1,2,3-triazol-1-yl)-1-(4-((2-(4-(trifluoromethoxy)styryl)oxazol-4-yl)methoxy)phenyl)butan-1-ol

This compound was synthesized as described in Example 2 (page 22 andcompound 22) of International Patent Publication no. WO 2006/032453.LRMS+H⁺: 501.2.

Compound 20:(E)-1-(4-((2-(4-bromo-2-fluorostyryl)oxazol-4-yl)methoxy)phenyl)-4-(1H-1,2,3-triazol-1-yl)butan-1-one

Step 1: (E)-3-(4-bromo-2-fluorophenyl)acrylamide

Oxalyl chloride (0.429 ml, 4.90 mmol) was added to a suspension of(E)-3-(4-bromo-2-fluorophenyl)acrylic acid (1 g, 4.08 mmol) in DCM (27.2ml) at 0° C. and DMF (8.74 μl, 0.122 mmol) was added. The temperaturewas brought to rt and let go for 2 h. The solvent was removed and theresidue taken in EA and the solvent was removed. It was taken again inEA and NH₄OH_(conc) (6.15 ml, 86 mmol) was added slowly. After stirringfor 30 min it was diluted with EA and the organic phase separated. Itwas washed with brine, Na₂SO₄ dried, filtered and the solvent removed togive 0.88 g of the title compound.

Step 2: (E)-2-(4-bromo-2-fluorostyryl)-4-(chloromethyl)oxazole

A mixture of (E)-3-(4-bromo-2-fluorophenyl)acrylamide (0.876 g, 3.59mmol) and 1,3-dichloropropan-2-one (0.911 g, 7.18 mmol) in toluene (7.18ml) was heated to reflux with a Dean-Stark for 24 h. The solvent wasremoved and the residue absorbed on SiO₂. Purification on ISCO using aRediSep® column (Hx-EA; 0-40%) gave 0.61 g of the title compound. ¹H NMR(400 MHz, CDCl₃) δ ppm 4.55 (d, J=0.78 Hz, 2H) 7.03 (d, J=16.82 Hz, 1H)7.28-7.35 (m, 2H) 7.38-7.47 (m, 1H) 7.58 (d, J=16.82 Hz, 1H) 7.66 (s,1H).

Step 3:(E)-1-(4-((2-(4-bromo-2-fluorostyryl)oxazol-4-yl)methoxy)phenyl)-4-(1H-1,2,3-triazol-1-yl)butan-1-one

This compound was prepared from the previous chloride and1-(4-hydroxyphenyl)-4-(1H-1,2,3-triazol-1-yl)butan-1-one in a similarfashion as compound 1 step 5. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.15(quint, J=7.20, Hz, 2H) 3.00 (t, J=7.24 Hz, 2H) 4.45 (t, J=7.24 Hz, 2H)5.14 (s, 2H) 7.15 (d, J=9.00 Hz, 2H) 7.27 (d, J=16.43 Hz, 1H) 7.45-7.55(m, 2H) 7.66 (dd, J=10.56, 1.96 Hz, 1H) 7.73 (s, 1H) 7.85-7.91 (m, 1H)7.92 (d, J=9.00 Hz, 2H) 8.17 (s, 1H) 8.29 (s, 1H). LRMS+H⁺: 511.1.

Compound 21:(E)-1-(4-((2-(4-bromo-2-fluorostyryl)oxazol-4-yl)methoxy)phenyl)-4-(1H-1,2,3-triazol-1-yl)butan-1-ol

This compound was prepared in a similar fashion as compound 17. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.42-1.62 (m, 2H) 1.68-1.81 (m, 1H) 1.81-1.94(m, 1H) 4.37 (t, J=7.04 Hz, 2H) 4.46-4.53 (m, 1H) 4.99 (s, 2H) 5.14 (d,J=4.30 Hz, 1H) 6.97 (d, J=8.61 Hz, 2H) 7.21 (d, J=8.61 Hz, 2H) 7.27 (d,J=16.43 Hz, 1H) 7.49 (s, 2H) 7.66 (dd, J=10.56, 1.96 Hz, 1H) 7.69 (d,J=0.78 Hz, 1H) 7.88 (t, J=8.41 Hz, 1H) 8.09 (s, 1H) 8.23 (s, 1H).LRMS+H⁺: 515.0913.

Compound 22:(E)-1-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)-4-(1H-1,2,3-triazol-1-yl)butan-1-one

This compound was prepared in a similar fashion as compound 20 with(E)-4-(chloromethyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole (seecompound 48). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.15 (quin, J=7.00 Hz, 2H)3.00 (t, J=7.04 Hz, 2H) 4.45 (t, J=7.04 Hz, 2H) 5.15 (s, 2H) 7.16 (d,J=9.00 Hz, 2H) 7.40 (d, J=16.82 Hz, 1H) 7.60 (d, J=16.43 Hz, 1H) 7.65(d, J=8.61 Hz, 1H) 7.72 (s, 1H) 7.78 (d, J=10.96 Hz, 1H) 7.93 (d, J=8.61Hz, 2H) 8.12-8.20 (m, 2H) 8.32 (s, 1H). LRMS+H⁺: 501.0.

Compound 23:(E)-1-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)-4-(1H-1,2,3-triazol-1-yl)butan-1-ol

NaBH₄ (2.4 mg, 0.064 mmol) was added to a solution of(E)-1-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)-4-(1H-1,2,3-triazol-1-yl)butan-1-one(0.016 g, 0.032 mmol) in MeOH (2.0 ml)-THF (2.0 ml). After 30 min, thesolvent was removed and the residue taken in EA and a NH₄Cl solution.The organic phase was separated, Na₂SO₄ dried, filtered and absorbed onSiO2. Purification on ISCO using a RediSep® column (Hx-EA; 40-100%) gave0.010 g of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.44-1.58(m, 2H) 1.68-1.81 (m, 1H) 1.82-1.95 (m, 1H) 4.37 (t, J=7.04 Hz, 2H)4.45-4.54 (m, 1H) 5.01 (s, 2H) 5.14 (d, J=4.30 Hz, 1H) 6.97 (d, J=8.61Hz, 2H) 7.18-7.25 (m, 2H) 7.39 (d, J=16.43 Hz, 1H) 7.59 (d, J=16.83 Hz,1H) 7.65 (d, J=8.22 Hz, 1H) 7.69 (s, 1H) 7.78 (d, J=10.17 Hz, 1H) 8.09(s, 1H) 8.16 (t, J=7.63 Hz, 1H) 8.27 (s, 1H). LRMS+H⁺—H₂O: 485.0.

Compound 24:(E)-1-(4-((2-(2-fluoro-4-nitrostyryl)oxazol-4-yl)methoxy)phenyl)-4-(1H-1,2,3-triazol-1-yl)butan-1-one

Step 1: (E)-ethyl 3-(2-fluoro-4-nitrophenyl)acrylate

Ethyl 2-(triphenylphosphoranylidene)acetate (4.12 g, 11.83 mmol) wasadded to a solution of 2-fluoro-4-nitrobenzaldehyde (1.00 g, 5.91 mmol)in THE (11.83 ml) and this was heated for 5 h. The solvent was removedand the residue diluted in toluene and purified on a short pad of SiO2Hx-EA (9-1). This was then treated with 5% mol of iodine in 50 ml oftoluene at 100° C. overnight. The solvent was removed to give 1.25 g ofthe title compound. ¹H NMR (400 MHz, CDCl3d) δ ppm 1.37 (t, J=7.24 Hz,3H) 4.31 (q, J=7.17 Hz, 2H) 6.68 (d, J=16.43 Hz, 1H) 7.68-7.76 (m, 1H)7.69-7.76 (m, 1H) 8.00 (dd, J=9.98, 2.15 Hz, 1H) 8.07 (dd, J=8.41, 2.15Hz, 1H).

Step 2: (E)-3-(2-fluoro-4-nitrophenyl)acrylamide

NaOH (3.92 ml, 7.84 mmol) was added to a solution of (E)-ethyl3-(2-fluoro-4-nitrophenyl)acrylate (1.25 g, 5.23 mmol) in THE (10.45 ml)followed by a few drops of MeOH until one phase was obtained. It washeated to 50° C. for 1 h. Then, HCl 10% quenched, diluted with EA,extracted 4× with EA and washed the combined organic phase with brine.The organic phase was Na₂SO₄ dried, filtered, absorbed on SiO₂ and thesolvent removed. This crude carboxylic acid was then converted to thetitle compound according to the procedure for the compound 20 step 1. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 6.90 (d, J=16.04 Hz, 1H) 7.36 (br. s., 1H)7.52 (d, J=16.04 Hz, 1H) 7.77 (br. s., 1H) 7.95 (t, J=8.02 Hz, 1H) 8.13(dd, J=8.61, 1.96 Hz, 1H) 8.19 (dd, J=10.56, 2.35 Hz, 1H).

Step 3: (E)-4-(chloromethyl)-2-(2-fluoro-4-nitrostyryl)oxazole

A mixture of (E)-3-(2-fluoro-4-nitrophenyl)acrylamide (0.100 g, 0.47mmol), and 1,3-dichloropropan-2-one (0.181 g, 1.42 mmol) in toluene(0.25 ml) was heated to 120° C. for 8 h. It was diluted with EA andabsorbed on SiO₂. Purification on ISCO using a RediSep® column (Hx-EA;0-70%) gave 0.071 g of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δppm 4.73 (s, 2H) 7.47 (d, J=16.43 Hz, 1H) 7.62 (d, J=16.43 Hz, 1H)8.09-8.15 (m, 2H) 8.18-8.29 (m, 3H).

Step 4:(E)-1-(4-((2-(2-fluoro-4-nitrostyryl)oxazol-4-yl)methoxy)phenyl)-4-(1H-1,2,3-triazol-1-yl)butan-1-one

This compound was prepared in a similar fashion as compound 25 with(E)-4-(chloromethyl)-2-(2-fluoro-4-nitrostyryl)oxazole and1-(4-hydroxyphenyl)-4-(1H-1,2,3-triazol-1-yl)butan-1-one. ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.15 (quin, J=7.00 Hz, 2H) 3.00 (t, J=7.04 Hz, 2H)4.45 (t, J=7.24 Hz, 2H) 5.16 (s, 2H) 7.16 (d, J=8.61 Hz, 2H) 7.48 (d,J=16.83 Hz, 1H) 7.62 (d, J=16.43 Hz, 1H) 7.72 (s, 1H) 7.93 (d, J=8.61Hz, 2H) 8.09-8.14 (d, 1H) 8.17 (s, 1H) 8.18-8.26 (d, 2H) 8.35 (s, 1H).HRMS+H⁺:478.1503

Compound 25:(E)-1-(4-((2-(2-fluoro-4-nitrostyryl)oxazol-4-yl)methoxy)phenyl)-4-(1H-1,2,3-triazol-1-yl)butan-1-ol

This compound was prepared in a similar fashion as compound 23 from theprevious ketone (no need of the microwave). ¹H NMR (400 MHz, DMSO-d₆) δppm 1.44-1.58 (m, 2H) 1.68-1.81 (m, 1H) 1.82-1.95 (m, 1H) 4.37 (t,J=7.04 Hz, 2H) 4.45-4.54 (m, 1H) 5.01 (s, 2H) 5.14 (d, J=4.30 Hz, 1H)6.97 (d, J=8.61 Hz, 2H) 7.18-7.25 (m, 2H) 7.39 (d, J=16.43 Hz, 1H) 7.59(d, J=16.83 Hz, 1H) 7.65 (d, J=8.22 Hz, 1H) 7.69 (s, 1H) 7.78 (d,J=10.17 Hz, 1H) 8.09 (s, 1H) 8.16 (t, J=7.63 Hz, 1H) 8.27 (s, 1H).LRMS+H⁺-H₂O: 462.0.

Compound 26:(E)-4-(4-(1H-1,2,3-triazol-1-yl)butyl)—N-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methyl)aniline

Step 1: 4-(4-nitrophenyl)but-3-yn-1-ol

To a degassed solution of Ph₃P (0.130 g, 0.495 mmol),1-bromo-4-nitrobenzene (5.00 g, 24.75 mmol) and4-(4-nitrophenyl)but-3-yn-1-ol (4.55 g, 23.80 mmol, 96% yield) in Et₃N(103 ml)-toluene (165 ml) was added copper (I) iodide (0.236 g, 1.238mmol) and PdCl₂(PPh₃)₂(0.521 g, 0.743 mmol). The mixture was heated to90° C. for 24 h at the end of which it was filtered and the solventremoved. The residue was diluted with a NH₄Cl solution and EA. Theorganic phase was separated and the aqueous phase extracted 2× with EA.The combined organic phases was washed with water, Na₂SO₄ dried,filtered and absorbed on SiO₂. Purification on ISCO using a RediSep®column (Hx-EA; 10-1000%) gave 4.55 g of the title compound.

Step 2: 4-(4-aminophenyl)butan-1-ol

A mixture of 4-(4-nitrophenyl)but-3-yn-1-ol (1.00 g, 5.23 mmol) and PtO₂(0.125 g) in EtOH (52 ml) was hydrogenated at 1 atmosphere and rt for 4h. The reaction was filtered and the solvent removed to give 0.77 g ofthe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.44 (m, 2H)1.44-1.53 (m, 2H) 2.38 (t, J=7.43 Hz, 2H) 3.35-3.41 (m, 2H) 4.32 (t,J=5.09 Hz, 1H) 4.77 (s, 1H) 6.41-6.51 (m, 2H) 6.82 (m, J=8.22 Hz, 2H).

Step 3:(E)-4-(4-(((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methyl)amino)phenyl)butan-1-oI

A mixture of (E)-4-(chloromethyl)-2-(4-(trifluoromethyl)styryl)oxazole(0.100 g, 0.348 mmol), 4-(4-aminophenyl)butan-1-ol (0.057 g, 0.348 mmol)and K₂CO₃ (0.072 g, 0.521 mmol) in DMF (0.695 ml) was heated at 75° C.overnight. It was diluted with a NH₄Cl solution and EA. The organicphase was separated and the aqueous extracted 2× with EA. They werecombined and washed with water, Na₂SO₄ dried, filtered, absorbed onSiO₂. Purification on ISCO using a RediSep® column (Hx-EA; 10-100%) gave0.077 g of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35-1.44(m, 2H) 1.45-1.55 (m, 2H) 2.40 (t, J=7.43 Hz, 2H) 3.38 (q, J=6.00 Hz,2H) 4.14 (d, J=5.87 Hz, 2H) 4.32 (t, J=5.09 Hz, 1H) 5.81 (t, J=5.87 Hz,1H) 6.56 (d, J=8.61 Hz, 2H) 6.90 (d, J=8.22 Hz, 2H) 7.30 (d, J=16.43 Hz,1H) 7.56 (d, J=16.43 Hz, 1H) 7.75 (d, J=8.22 Hz, 2H) 7.90-8.00 (m, 3H).

Step 4:(E)-4-(4-azidobutyl)—N-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methyl)aniline

This compound was prepared in a similar fashion as compound 1 step 2(method B) with(E)-4-(4-(((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methyl)amino)phenyl)butan-1-olto give the title compound. LRMS+H⁺: 442.3

Step 5:(E)-4-(4-(1H-1,2,3-triazol-1-yl)butyl)-N-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methyl)aniline

This compound was prepared in a similar fashion as compound 1 step 3with vinyl acetate and(E)-4-(4-azidobutyl)—N-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methyl)aniline.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51 (quin, J=7.63 Hz, 2H) 1.83 (quin,J=7.34 Hz, 2H) 2.57 (t, J=7.43 Hz, 2H) 4.40 (t, J=7.04 Hz, 2H) 7.11-7.22(m, 3H) 7.37-7.49 (m, 3H) 7.61-7.78 (m, 6H) 8.09-8.16 (m, 1H) 8.76 (s,1H) 10.07 (s, 1H). LRMS+H⁺: 468.1.

Compound 27:(E)-4-(4-(1H-1,2,3-triazol-1-yl)butyl)-N-((2-(4-bromo-2-fluorostyryl)oxazol-4-yl)methyl)aniline

Step 1:(E)-4-(4-(((2-(4-bromo-2-fluorostyryl)oxazol-4-yl)methyl)amino)phenyl)butan-1-ol

This compound was prepared in a similar fashion as compound 26 step 3with (E)-2-(4-bromo-2-fluorostyryl)-4-(chloromethyl)oxazole. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.34-1.45 (m, 2H) 1.45-1.55 (m, 2H) 2.40 (t, J=7.43Hz, 2H) 3.38 (q, J=6.26 Hz, 2H) 4.14 (d, J=6.26 Hz, 2H) 4.32 (t, J=5.28Hz, 1H) 5.82 (t, J=1.00 Hz, 1H) 6.56 (d, J=8.22 Hz, 2H) 6.89 (d, J=8.22Hz, 2H) 7.23 (d, J=16.43 Hz, 1H) 7.42-7.52 (m, 2H) 7.65 (dd, J=10.56,1.96 Hz, 1H) 7.86 (t, J=1.00 Hz, 1H) 7.96 (s, 1H).

Step 2:(E)-4-(4-azidobutyl)—N-((2-(4-bromo-2-fluorostyryl)oxazol-4-yl)methyl)aniline

This compound was prepared in a similar fashion as compound 1 step 2(method B).

Step 3:(E)-4-(4-(1H-1,2,3-triazol-1-yl)butyl)-N-((2-(4-bromo-2-fluorostyryl)oxazol-4-yl)methyl)aniline

This compound was prepared in a similar fashion as compound 1 step 3with(E)-4-(4-azidobutyl)—N-((2-(4-bromo-2-fluorostyryl)oxazol-4-yl)methyl)anilin.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32-1.48 (m, 2H) 1.72-1.81 (m, 2H) 2.41(t, J=7.63 Hz, 2H) 4.11 (d, J=5.87 Hz, 2H) 4.35 (t, J=7.04 Hz, 2H) 5.82(t, J=5.87 Hz, 1H) 6.54 (d, J=8.22 Hz, 2H) 6.86 (d, J=8.61 Hz, 2H)7.17-7.25 (m, 1H) 7.38-7.53 (m, 2H) 7.61-7.66 (m, 1H) 7.68 (s, 1H)7.79-7.89 (m, 1H) 7.94 (s, 1H) 8.08 (s, 1H). LRMS+H⁺: 496.1.

Compound 28:4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-(trifluoromethyl)phenyl)oxazole

Step 1: 4-(chloromethyl)-2-(4-(trifluoromethyl)phenyl)oxazole

A mixture of 4-(trifluoromethyl)benzamide (1.00 g, 5.29 mmol) and1,3-dichloropropan-2-one (1.343 g, 10.57 mmol) in toluene (15.11 ml) washeated to reflux 24 h. Added 0.5 eq more of 1,3-dichloropropan-2-one andlet go overnight at reflux. The solvent was removed, the residueabsorbed on SiO₂ and purified on ISCO using a RediSep® column (Hx-EA;0-70%). This gave 0.62 g of the title compound. ¹H NMR (400 MHz, CDCl₃)δ ppm 4.60 (d, =0.78 Hz, 2H) 7.74 (d, J=8.22 Hz, 2H) 7.76-7.78 (d, 1H)8.17 (d, J=7.83 Hz, 2H).

Step 2:4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-(trifluoromethyl)phenyl)oxazole

NaH 60% (6.6 mg, 0.16 mmol) was added to a solution of4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenol (0.030 g, 0.138 mmol) in DMF(0.690 ml) at 0° C. Bring to rt and4-(chloromethyl)-2-(4-(trifluoromethyl)phenyl)oxazole (0.042 g, 0.159mmol) was added and let go overnight. The reaction was quenched with aNH₄Cl solution and diluted with EA. The organic phase was separated andthe aqueous phase extracted with EA. They were combined and washed withbrine, dried over Na₂SO₄, filtered and absorbed on SiO₂. Purification onISCO using a RediSep® column (Hx-EA; 0-100%) gave 0.042 g of the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.58-1.70 (m, 2H) 1.88-2.00 (m,1H) 2.62 (t, J=7.43 Hz, 2H) 4.40 (t, J=7.24 Hz, 2H) 5.08 (d, J=0.78 Hz,2H) 6.90-6.97 (m, 2H) 7.09 (d, J=8.61 Hz, 2H) 7.50 (d, J=0.78 Hz, 1H)7.70-7.74 (m, 2H) 7.75 (s, 1H) 7.79 (s, 1H) 8.18 (d, J=8.22 Hz, 2H).

Compound 29:(E)-N-(4-(4-hydroxybutyl)phenyl)-2-(4-(trifluoromethyl)styryl)oxazole-4-carboxamide

To a mixture of (E)-2-(4-(trifluoromethyl)styryl)oxazole-4-carboxylicacid (0.263 g, 0.929 mmol) from PCT Int. Appl., 2004096796,triethylamine (0.25 ml, 1.85 mmol), 4-(4-aminophenyl)butan-1-ol (0.184g, 1.11 mmol) and HOBT (0.171 g, 1.114 mmol) in DMF (1.857 ml) was addedEDC (0.196 g, 1.022 mmol). After 5 h it was diluted with a NH₄Clsolution and EA. The organic phase was separated and the aqueousextracted 2× with EA. They were combined and washed with water, It wasdried over Na₂SO₄, filtered and absorbed on SiO₂. Purification on ISCOusing a RediSep® column (Hx-EA; 10-100%) gave 0.174 g of the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.36-1.48 (m, 2H) 1.52-1.63(m, 2H) 2.55 (t, J=7.63 Hz, 2H) 3.37-3.44 (m, 2H) 4.36 (t, J=5.09 Hz,1H) 7.17 (d, J=8.61 Hz, 2H) 7.36 (d, J=16.43 Hz, 1H) 7.70 (d, J=8.61 Hz,2H) 7.74 (d, J=16.43 Hz, 1H) 7.79 (m, J=8.22 Hz, 2H) 7.98 (m, J=8.22 Hz,2H) 8.81 (s, 1H) 10.08 (s, 1H).

Compound 30:(E)-N-(4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenyl)-2-(4-(trifluoromethyl)styryl)oxazole-4-carboxamide

Step 1:(E)-N-(4-(4-azidobutyl)phenyl)-2-(4-(trifluoromethyl)styryl)oxazole-4-carboxamide

This compound was prepared according to Method B of compound 1 step 2and(E)-N-(4-(4-hydroxybutyl)phenyl)-2-(4-(trifluoromethyl)styryl)oxazole-4-carboxamide.¹H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.68 (m, 4H) 2.58 (t, J=7.24 Hz,2H) 3.35 (t, J=6.65 Hz, 2H) 7.18 (d, J=8.22 Hz, 2H) 7.36 (d, J=16.43 Hz,1H) 7.69-7.77 (m, 3H) 7.80 (m, J=8.22 Hz, 2H) 7.98 (m, J=8.22 Hz, 2H)8.82 (s, 1H) 10.09 (s, 1H).

Step 2:(E)-N-(4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenyl)-2-(4-(trifluoromethyl)styryl)oxazole-4-carboxamide

This compound was prepared according to the procedure described forcompound 1 step 3 with the previous intermediate. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.51 (quin, J=7.40 Hz, 2H) 1.83 (quin, J=7.34 Hz, 1H)2.57 (t, J=7.63 Hz, 2H) 4.40 (t, J=6.85 Hz, 2H) 7.15 (d, J=8.22 Hz, 2H)7.36 (d, J=16.43 Hz, 1H) 7.67-7.77 (m, 4H) 7.79 (d, J=8.61 Hz, 2H) 7.98(d, J=8.22 Hz, 2H) 8.12 (s, 1H) 8.81 (s, 1H) 10.08 (s, 1H). LRMS+H⁺:482.1.

Compound 31:(E)-5-(dimethylamino)-N-(2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethyl)naphthalene-1-sulfonamide

Step 1: N-(but-3-yn-1-yl)-5-(dimethylamino)naphthalene-1-sulfonamide

MeOH (0.013 ml, 0.315 mmol) was added to a mixture of but-3-yn-1-aminehydrochloride (0.075 g, 0.710 mmol), triethylamine (1.0 ml, 7.14 mmol)and 5-(dimethylamino)naphthalene-1-sulfonyl chloride (0.085 g, 0.315mmol) in THE (2.5 ml).

After 5 min it was diluted with EA-water and the organic phase wasseparated and washed with water. It was then dried over Na₂SO₄, filteredand the solvent removed. Purification on ISCO using a RediSep® column(Hx-EA; 0-60%) gave 0.055 g of the title compound. LRMS+H⁺: 303.1.

Step 2:(E)-5-(dimethylamino)-N-(2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethyl)naphthalene-1-sulfonamide

This compound was prepared in a similar fashion as compound 8 with(E)-4((4-(4-azidobutyl)phenoxy)methyl)-2-(4-(trifluoromethyl)styryl)oxazoleand the previous intermediate. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.45(quin, J=7.20 Hz, 2H) 1.71 (quin, J=7.34 Hz, 2H) 2.68 (t, J=7.43 Hz, 2H)3.04 (q, J=6.70 Hz, 2H) 4.22 (t, J=7.04 Hz, 2H) 4.98 (s, 2H) 6.93 (d,J=8.61 Hz, 2H) 7.08 (d, J=8.61 Hz, 2H) 7.24 (d, J=7.43 Hz, 1H) 7.34 (d,J=16.43 Hz, 1H) 7.53-7.64 (m, 3H) 7.67 (s, 1H) 7.76 (d, J=8.61 Hz, 2H)7.95 (d, J=8.22 Hz, 2H) 8.05 (t, J=5.67 Hz, 1H) 8.10 (dd, J=7.43, 1.17Hz, 1H) 8.23 (s, 1H) 8.27 (d, J=8.61 Hz, 1H) 8.45 (d, J=8.61 Hz, 1H).LRMS+H⁺: 745.2.

Compound 32:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-methoxystyryl)oxazole

Step 1: (E)-4-(chloromethyl)-2-(4-methoxystyryl)oxazole

(E)-3-(4-methoxyphenyl)acrylamide, prepared from the correspondingcarboxylic acid according to compound 3 step 1, (359 mg, 2,026 mmol) and1,3-dichloropropan-2-one (514 mg, 4.05 mmol) in toluene (6.2 ml) washeated at 145° C. with a Dean-Stark for 17 h. The mixture wasconcentrated under reduced pressure and the residue was absorbed onsilica gel and purified on ISCO using a RediSep® column (Hx-EA; 0-35%)to give 420 mg of the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.85(s, 3H) 4.54 (d, J=0.78 Hz, 2H) 6.79 (d, J=16.43 Hz, 1H) 6.90-6.95 (m,2H) 7.45-7.53 (m, 3H) 7.61 (s, 1H)

Step 2:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-methoxystyryl)oxazole

A mixture of (E)-4-(chloromethyl)-2-(4-methoxystyryl)oxazole (100 mg,0.400 mmol), 4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenol (96 mg, 0.441mmol) and K₂CO₃ (60.9 mg, 0.441 mmol) in DMF (653 μl, 8.43 mmol) washeated at 75° C. for 3 hrs. It was cooled to rt and the compoundprecipitated. It was heated to obtain a solution and MeOH (653 μl, 16.14mmol) and water (1088 μl, 60.4 mmol) were added. Cooled to 20° C. andstirred for 45 min. The solids were collected on Buchner and the cakewas washed with water (2×1 mL) and dried at 35° C. to give 0.144 g ofthe title compound. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.54 (m, 2H)1.81 (quin, J=7.34 Hz, 2H) 2.52-2.57 (m, 2H) 3.79 (s, 3H) 4.39 (t,J=7.04 Hz, 2H)4.95 (s, 2H) 6.89-7.04 (m, 5H) 7.06-7.13 (m, 2H) 7.47 (d,J=16.43 Hz, 1H) 7.62-7.72 (m, 3H) 8.09-8.17 (m, 2H). LRMS+H)+. 431.1.

Compound 33:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-bromostyryl)oxazole

Step 1: (E)-2-(4-bromostyryl)-4-(chloromethyl)oxazole

(E)-3-(4-bromophenyl)acrylamide prepared from the correspondingcarboxylic acid according to compound 3 step 1 and1,3-dichloropropan-2-one gave the title compound according to compound32 step 1. ¹H NMR (400 MHz, CDCl₃) δ ppm 4.54 (d, J=0.78 Hz, 2H) 6.91(d, J=16.04 Hz, 1H) 7.39 (m, J=8.61 Hz, 2H) 7.48 (d, J=16.43 Hz, 1H)7.53 (m, J=8.61 Hz, 2H) 7.64 (s, 1H).

Step 2:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-bromostyryl)oxazole

(E)-2-(4-bromostyryl)-4-(chloromethyl)oxazole was reacted with4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenol according to the procedure forcompound 1 step 5. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48 (quin, J=7.63Hz, 2H) 1.81 (quin, J=7.34 Hz, 2H) 2.52-2.58 (m, 2H) 4.39 (t, J=7.04 Hz,2H) 4.97 (s, 2H) 6.93 (d, J=8.61 Hz, 2H) 7.09 (d, J=8.61 Hz, 2H) 7.21(d, J=16.43 Hz, 1H) 7.51 (d, J=16.43 Hz, 1H) 7.57-7.65 (m, 2H) 7.69 (d,J=8.61 Hz, 3H) 8.11 (d, J=0.78 Hz, 1H) 8.20 (s, 1H). HRMS+H⁺: 481.1037.

Compound 34:(E)-4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyldiethylcarbamate

Diethylcarbamic chloride (6.8 μl, 0.054 μmmol) was added to a suspensionof(E)-4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butan-1-ol(0.015 g, 0.036 mmol) in pyridine (0.012 ml) and the solution was heated8 h at 100° C. The solvent was removed and the residue purified on ISCOusing a RediSep® column (DCM-MeOH; 0-20%) to give 0.012 g of the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (t, J=7.04 Hz, 6H)1.46-1.65 (m, 4H) 2.51-2.58 (m, 2H) 3.19 (q, J=7.04 Hz, 4H) 3.99 (t,J=6.06 Hz, 2H) 4.99 (s, 2H) 6.95 (d, J=8.61 Hz, 2H) 7.12 (d, J=8.61 Hz,2H) 7.34 (d, J=16.43 Hz, 1H) 7.62 (d, J=16.43 Hz, 1H) 7.76 (d, J=8.22Hz, 2H) 7.95 (d, J=8.22 Hz, 2H) 8.24 (s, 1H). LRMS+H⁺: 517.2.

Compound 35:(E)-4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butylmorpholine-4-carboxylate

This compound was prepared in a similar fashion as compound 34 withmorpholine-4-carbonyl chloride. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.43-1.64 (m, 4H) 2.51-2.57 (m, 2H) 3.53 (t, J=4.89 Hz, 4H) 3.95-4.04(m, 2H) 4.99 (s, 2H) 6.95 (d, J=8.61 Hz, 2H) 7.12 (d, J=8.22 Hz, 2H)7.34 (d, J=16.43 Hz, 1H) 7.62 (d, J=16.43 Hz, 1H) 7.76 (d, J=8.22 Hz,2H) 7.95 (d, J=7.83 Hz, 2H). LRMS+H⁺: 531.2.

Compound 36:(E)-4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyldimethylcarbamate

This compound was prepared in a similar fashion as compound 34 withdimethylcarbamic chloride. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.47-1.64 (m,4H) 2.51-2.57 (m, 2H) 2.81 (br. s., 6H) 3.93-4.00 (m, 2H) 4.99 (s, 2H)6.95 (d, J=8.61 Hz, 2H) 7.12 (d, J=8.61 Hz, 2H) 7.34 (d, J=16.43 Hz, 1H)7.62 (d, J=16.43 Hz, 1H) 7.76 (d, J=8.61 Hz, 2H) 7.95 (d, J=8.22 Hz, 2H)8.24 (s, 1H). LRMS+H⁺: 489.2.

Compounds 37 to 48

The following compounds (37-48) were prepared in three steps accordingto the following procedure. Step 1: the acrylamide is prepared from thecorresponding carboxylic acid according to the procedure of compound 3step 1; the chloromethyl oxazole is prepared from the correspondingacrylamide according to the procedure of compound 3 step 2 (or it couldbe prepared without solvent at 130° C. until completion). The last stepis done with 4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenol and thecorresponding chloromethyl oxazole according to Compound 1 step 5.

Compound 37:(E)-4-(2-(4-((4(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)benzonitrile

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48 (quin, J=7.63 Hz, 2H) 1.81 (quin,J=7.24 Hz, 2H) 2.52-2.57 (m, 2H) 4.39 (t, J=7.04 Hz, 2H) 4.98 (s, 2H)6.94 (m, J=8.61 Hz, 2H) 7.09 (m, J=8.61 Hz, 2H) 7.37 (d, J=16.43 Hz, 1H)7.60 (d, J=16.43 Hz, 1H) 7.70 (s, 1H) 7.87 (d, J=8.61 Hz, 2H) 7.93 (d,J=8.22 Hz, 2H) 8.11 (s, 1H) 8.24 (s, 1H). LRMS+H⁺: 426.2.

Compound 38:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-chlorostyryl)oxazole

¹H NMR (400 MHz, DMSO-δ₆) δ ppm 1.48 (quin, J=7.63 Hz, 2H) 1.81 (quin,J=7.34 Hz, 2H) 2.52-2.57 (m, 2H) 4.39 (t, J=7.04 Hz, 2H) 4.97 (s, 2H)6.93 (m, J=8.61 Hz, 2H) 7.09 (d, J=8.61 Hz, 2H) 7.19 (d, J=16.43 Hz, 1H)7.47 (d, J=8.61 Hz, 2H) 7.53 (d, J=16.43 Hz, 1H) 7.68-7.72 (m, 1H) 7.76(d, J=8.61 Hz, 2H) 8.11 (s, 1H) 8.19 (s, 1H). LRMS+H⁺: 435.1.

Compound 39:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-fluorostyryl)oxazole

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48 (quin, J=7.63 Hz, 2H) 1.81 (quin,J=7.34 Hz, 2H) 2.52-2.57 (m, 2H) 4.39 (t, J=7.04 Hz, 2H) 4.96 (s, 2H)6.93 (d, J=8.22 Hz, 2H) 7.05-7.18 (m, 3H) 7.25 (t, J=8.80 Hz, 2H) 7.53(d, J=16.43 Hz, 1H) 7.70 (s, 1H) 7.79 (dd, J=8.61, 5.87 Hz, 2H) 8.11 (s,1H) 8.18 (s, 1H). LRMS+H⁺: 419.1.

Compound 40:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-nitrostyryl)oxazole

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48 (quin, J=7.63 Hz, 2H) 1.81 (quin,J=7.34 Hz, 2H) 2.52-2.58 (m, 2H) 4.39 (t, J=7.04 Hz, 2H) 4.99 (s, 2H)6.94 (d, J=8.61 Hz, 2H) 7.09 (d, J=8.61 Hz, 2H) 7.42 (d, J=16.82 Hz, 1H)7.66 (d, J=16.43 Hz, 1H) 7.70 (s, 1H) 8.01 (d, J=9.00 Hz, 2H) 8.11 (s,1H) 8.20-8.31 (m, 3H). LRMS+H⁺: 446.1.

Compound 41:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluorostyryl)oxazole

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48 (quin, J=7.63 Hz, 2H) 1.81 (quin,J=7.24 Hz, 2H) 2.51-2.57 (m, 2H) 4.39 (t, J=7.04 Hz, 2H) 4.98 (s, 2H)6.94 (d, J=8.61 Hz, 2H) 7.09 (d, J=8.61 Hz, 2H) 7.23 (d, J=16.82 Hz, 1H)7.26-7.33 (m, 2H) 7.39-7.48 (m, 1H) 7.58 (d, J=16.82 Hz, 1H) 7.70 (s,1H) 7.91 (t, J=7.83 Hz, 1H) 8.11 (s, 1H) 8.21 (s, 1H). LRMS+H⁺: 419.1.

Compound 42:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-nitrostyryl)oxazole

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48 (quin, J=7.63 Hz, 2H) 1.81 (quin,J=7.34 Hz, 2H) 2.52-2.58 (m, 2H) 4.39 (t, J=7.04 Hz, 2H) 4.99 (s, 2H)6.94 (d, J=8.61 Hz, 2H) 7.09 (d, J=8.22 Hz, 2H) 7.24 (d, J=16.04 Hz, 1H)7.59-7.67 (m, 1H) 7.70 (s, 1H) 7.74-7.83 (m, 2H) 8.06 (d, J=8.22 Hz, 2H)8.11 (s, 1H) 8.25 (s, 1H). LRMS+H⁺: 446.1.

Compound 43:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(3-nitrostyryl)oxazole

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48 (quin, J=7.63 Hz, 2H) 1.81 (quin,J=7.24 Hz, 2H) 2.52-2.57 (m, 2H) 4.39 (t, J=7.04 Hz, 2H) 4.99 (s, 2H)6.94 (d, J=8.61 Hz, 2H) 7.10 (d, J=8.61 Hz, 2H) 7.41 (d, J=16.43 Hz, 1H)7.63-7.76 (m, 3H) 8.11 (s, 1H) 8.16-8.28 (m, 3H) 8.57 (s, 1H). LRMS+H⁺:446.1.

Compound 44:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(trifluoromethyl)styryl)oxazole

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48 (quin, J=7.63 Hz, 2H) 1.81 (quin,J=7.34 Hz, 2H) 2.52-2.57 (m, 2H) 4.39 (t, J=7.04 Hz, 2H) 4.99 (s, 2H)6.94 (d, J=8.61 Hz, 2H) 7.09 (d, J=8.61 Hz, 2H) 7.31 (d, J=16.04 Hz, 1H)7.55-7.63 (m, 1H) 7.66-7.78 (m, 3H) 7.81 (d, J=7.83 Hz, 1H) 8.07-8.17(m, 2H) 8.24 (s, 1H). LRMS+H⁺: 469.1.

Compound 45:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2,4-difluorostyryl)oxazole

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48 (quin, J=7.63 Hz, 2H) 1.81 (quin,J=7.24 Hz, 2H) 2.52-2.57 (m, 2H) 4.39 (t, J=7.04 Hz, 2H) 4.97 (s, 2H)6.94 (d, J=8.61 Hz, 2H) 7.09 (d, J=8.61 Hz, 2H) 7.14-7.25 (m, 2H) 7.36(ddd, J=11.35, 9.19, 2.54 Hz, 1H) 7.52 (d, J=16.82 Hz, 1H) 7.70 (s, 1H)7.99 (td, J=8.80, 7.04 Hz, 1H) 8.11 (s, 1H) 8.21 (s, 1H). LRMS+H⁺:437.1.

Compound 46:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2,6-difluorostyryl)oxazole

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48 (quin, J=7.63 Hz, 2H) 1.81 (quin,J=7.34 Hz, 2H) 2.52-2.56 (m, 2H) 4.39 (t, J=7.04 Hz, 2H) 4.98 (s, 2H)6.94 (d, J=8.61 Hz, 2H) 7.09 (d, J=8.61 Hz, 2H) 7.16 (d, J=16.82 Hz, 1H)7.23 (t, J=8.80 Hz, 2H) 7.42-7.54 (m, 2H) 7.70 (s, 1H) 8.08-8.13 (m, 1H)8.25 (s, 1H). LRMS+H⁺: 437.1.

Compound 47:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-styryloxazole

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48 (quin, J=7.63 Hz, 2H) 1.81 (quin,J=7.34 Hz, 2H) 2.52-2.57 (m, 2H) 4.39 (t, J=7.04 Hz, 2H) 4.97 (s, 2H)6.94 (d, J=8.61 Hz, 2H) 7.09 (d, J=8.22 Hz, 2H) 7.16 (d, J=16.43 Hz, 1H)7.33-7.47 (m, 3H) 7.53 (d, J=16.43 Hz, 1H) 7.66-7.77 (m, 3H) 8.11 (s,1H) 8.18 (s, 1H). LRMS+H⁺: 401.2.

Compound 48:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

¹H NMR (500 MHz, CDCl₃) δ ppm 1.60-1.67 (m, 2H) 1.95 (dt, J=15.05, 7.45Hz, 2H) 2.61 (t, J=7.57 Hz, 2H) 4.40 (t, J=7.09 Hz, 2H) 5.03 (d, J=0.95Hz, 2H) 6.91-6.94 (m, 2H) 7.06-7.10 (m, 2H) 7.14 (d, J=16.71 Hz, 1H)7.39 (d, J=10.40 Hz, 1H) 7.45 (d, J=8.51 Hz, 1H) 7.50 (d, J=0.95 Hz, 1H)7.62-7.72 (m, 4H). LRMS+H⁺: 487.3.

Compound 49:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(3-(trifluoromethyl)styryl)oxazole

Step 1: (E)-3-(3-(trifluoromethyl)phenyl)acrylamide

This compound was prepared in a similar fashion as compound 3 step 1starting with (E)-3-(3-(trifluoromethyl)phenyl)acrylic acid. LRMS+H⁺:216.2.

Step 2: (E)-4-(chloromethyl)-2-(3-(trifluoromethyl)styryl)oxazole

This compound was prepared in a similar fashion as compound 3 step 2.LRMS+H⁺: 288.1.

Step 3:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(3-(trifluoromethyl)styryl)oxazole

This compound was prepared in a similar fashion as compound 3 step 3with the previous intermediate and4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenol. ¹H NMR (500 MHz, CDCl₃) δ ppm1.60-1.68 (m, 2H) 1.95 (dt, J=14.90, 7.53 Hz, 2H) 2.62 (t, J=7.57 Hz,2H) 4.40 (t, J=7.09 Hz, 2H) 5.03 (d, J=0.95 Hz, 2H) 6.93 (d, J=8.50 Hz,2H) 7.01 (d, J=16.39 Hz, 1H) 7.08 (d, J=8.50 Hz, 2H) 7.50 (d, J=0.95 Hz,1H) 7.53 (t, J=7.60 Hz, 1H) 7.56 (d, J=16.71 Hz, 1H) 7.59-7.62 (m, 1H)7.67-7.73 (m, 3H) 7.77 (s, 1H). LRMS+H⁺: 469.3.

Compound 50:(E)-4-((4-(3-(1H-1,2,3-triazol-1-yl)propyl)phenoxy)methyl)-2-(4-(trifluoromethyl)styryl)oxazole

Step 1:(E)-3-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)propan-1-ol

To a solution of 4-(3-hydroxypropyl)phenol (116 mg, 0.765 mmol) in DMF(6953 μl) was added NaH (64.0 mg, 1.599 mmol). After 30 min,(E)-4-(chloromethyl)-2-(4-(trifluoromethyl)styryl)oxazole (200 mg, 0.695mmol) was added to the chilled solution. After 2 h at rt the mixture waspoured into water and extracted with EA. The organic layer was washedwith water, 1N NaOH then brine, dried over Na₂SO₄, filtered andconcentrated. The residue was adsorbed onto silica gel and purified byISCO using a RediSep® column (Hx_EA; 0-100%) to afford 0.186 mg of thetitle compound. LRMS+H⁺: 404.3.

Step 2:(E)-4-((4-(3-iodopropyl)phenoxy)methyl)-2-(4-(trifluoromethyl)styryl)oxazole

To a chilled solution of(E)-3-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)propan-1-ol(186 mg, 0.461 mmol) in EA (4.61 ml) was added triethylamine (96 μl,0.692 mmol) and methanesulfonyl chloride (53.9 μl, 0.692 mmol) dropwise.After 30 min at 0° C., the mixture was allowed to warm to rt. After 1 hmore methanesulfonyl chloride (6 μl) and triethylamine (10 μl) wereadded and stirred overnight at rt. More methanesulfonyl chloride (10 μl)and triethylamine (20 μl) were added and stirred 1.5 h. The mixture waswashed with ice water and then brine. The organic layer was dried overNa₂SO₄, filtered and concentrated to afford(E)-3-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)propylmethanesulfonate (235 mg). To solution of the previous adduct in acetone(2.102 ml) was added Nal (366 mg, 2.440 mmol) and the mixture wasstirred at reflux for 1.5 h. The concentrated residue was dissolved inethyl acetate (20 ml), washed with water, aq. sodium thiosulfate thenbrine. The organic layer was dried over Na₂SO₄, filtered andconcentrated to afford 251 mg of the title compound. LRMS+H⁺: 5142.

Step 3:(E)-4-((4-(3-(1H-1,2,3-triazol-1-yl)propyl)phenoxy)methyl)-2-(4-(trifluoromethyl)styryl)oxazole

To solution of(E)-4-((4-(3-iodopropyl)phenoxy)methyl)-2-(4-(trifluoromethyl)styryl)oxazole(250 mg, 0.488 mmol) and 1H-1,2,3-triazole (42.4 μl, 0.732 mmol) in DMF(4880 μl) was added K₂CO₃ (101 mg, 0.732 mmol). The mixture was stirredat 60° C. over the weekend for 48 h. The mixture was diluted with ethylacetate (20 ml), washed with water then brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby ISCO using a RediSep® column (Hx-EA; 0-100%) to give 0.095 g of thetitle compound. ¹H NMR (500 MHz, CDCl₃) δ ppm 2.25 (quin, J=7.25 Hz, 2H)2.62 (t, J=7.41 Hz, 2H) 4.40 (t, J=7.09 Hz, 2H) 5.04 (d, J=0.95 Hz, 2H)6.93-6.97 (m, 2H) 7.03 (d, J=16.39 Hz, 1H) 7.10-7.14 (m, 2H) 7.53 (s,1H) 7.57 (d, J=16.39 Hz, 1H) 7.61-7.69 (m, 4H) 7.73 (s, 1H) 7.70 (s,1H). LRMS+H⁺: 455.3.

Compound 51:(E)-2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-imidazol-2-yl)ethanol

This compound was prepared according to Example 17 (page 98) ofInternational Patent Publication no. WO 01/77107. LRMS+H⁺: 512.3.

Compound 52:(E)-2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-imidazol-2-yl)ethanamine

To a solution of(E)-2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-imidazol-2-yl)ethanol(100 mg, 0.195 mmol), triphenylphosphine (56.4 mg, 0.215 mmol) andisoindoline-1,3-dione (31.6 mg, 0.215 mmol) in THE (1.955 ml) was addedDIAD (119 mg, 0.586 mmol). The mixture was stirred at rt for 3 h. Thereaction was diluted with EA and washed with 1N NaOH aq., brine, driedover Na₂SO₄, filtered and concentrated. This residue was suspended inEtOH (5 ml, 86 mmol) and treated with 2-aminoethanol (11.94 mg, 0.195mmol) at reflux for 1 h and the suspension was left at rt over theweekend. The mixture was concentrated, diluted with EA, washed withwater then brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by ISCO using a RediSep® column (DCM-MeOH; 0-30%)to give 0.065 g of the title compound. Reference: PCT 2003031442. ¹H NMR(500 MHz, CDCl₃) δ ppm 1.57-1.65 (m, 2H) 1.71-1.79 (m, 2H) 2.60 (t,J=7.41 Hz, 2H) 2.76 (t, J=6.62 Hz, 2H) 3.15 (t, J=6.46 Hz, 2H) 3.85 (t,J=7.25 Hz, 2H) 5.03 (d, J=0.95 Hz, 2H) 6.81 (d, J=1.26 Hz, 1H) 6.90-6.97(m, 3H) 7.02 (d, J=16.39 Hz, 1H) 7.06-7.11 (m, 2H) 7.56 (d, J=16.71 Hz,1H) 7.61-7.68 (m, 4H) 7.69 (s, 1H).

Compound 53:(E)-2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-imidazol-2-yl)ethyldimethylcarbamate

To a chilled solution of(E)-2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-imidazol-2-yl)ethanol(16 mg, 0.031 mmol) and triethylamine (6.50 μL, 0.047 mmol) in THE (2ml) was added dimethylcarbamic chloride (3.15 μL, 0.034 mmol). Themixture was allowed to stir at RT for 5 h. Added more Et₃N (43.3 μL,0.311 mmol) and dimethylcarbamic chloride (14.31 μL, 0.155 mmol) andstirred for two days. It was then heated to 50° C. for 10 h. The mixturewas partitioned between EA and dilute NaHCO₃ then extracted with EA(3×50 ml). The combined organic phases were dried over Na₂SO₄, filteredand concentrated. The residue was purified by ISCO using a RediSep®column (Hx-EA; 0-100%) then switch to DCM-MeOH (0-60%) to give 0.0055 gof the title compound. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.57-1.66 (m, 2H)1.71-1.81 (m, 2H) 2.59 (t, J=7.57 Hz, 2H) 2.84-2.97 (m, 6H) 3.02 (t,J=7.25 Hz, 2H) 3.89 (t, J=7.09 Hz, 2H) 4.42 (t, J=7.25 Hz, 2H) 5.03 (d,J=0.95 Hz, 2H) 6.81 (d, J=1.26 Hz, 1H) 6.89-6.96 (m, 2H) 6.97 (d, J=1.26Hz, 1H) 7.02 (d, J=16.39 Hz, 1H) 7.05-7.12 (m, 2H) 7.56 (d, J=16.39 Hz,1H) 7.60-7.67 (m, 4H) 7.69 (s, 1H). LRMS+H⁺: 583.3.

Compound 54:(E)-N-(2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-imidazol-2-yl)ethyl)methanesulfonamide

To a solution of(E)-2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-imidazol-2-yl)ethanamine(35 mg, 0.069 mmol) in pyridine (0.5 ml) was added methanesulfonylchloride (6.68 μl, 0.086 mmol). The milky suspension was stirred at rtfor 1.5 h and heated to 50° C. for 1 h. Added more methanesulfonylchloride (6.68 μl, 0.086 mmol) and stirred at rt for 2 h then heated to50° C. for 1 h and let go overnight at rt. The mixture was partitionedwith EA and water then extracted with EA twice. The combine organicphases were dried over Na₂SO₄, filtered and concentrated. The residuewas purified by ISCO using a RediSep® column with DCM-MeOH (0-30%) togive 0.025 g of the title compound. ¹H NMR (500 MHz, CDCl₃) δ ppm1.55-1.69 (m, 2H) 1.69-1.80 (m, 2H) 2.60 (t, J=7.41 Hz, 2H) 2.89 (br.s., 2H) 2.96 (s, 3H)₃.52-3.64 (m, 2H) 3.83 (t, J=7.09 Hz, 2H) 5.03 (d,J=0.95 Hz, 2H) 6.12 (br. s., 1H) 6.83 (s, 1H) 6.86-6.98 (m, 3H) 7.02 (d,J=16.39 Hz, 1H) 7.05-7.12 (m, 2H) 7.56 (d, J=16.39 Hz, 1H) 7.59-7.68 (m,4H) 7.70 (s, 1H). LRMS+H⁺: 589.3.

Compound 55:(E)-1,1,1-trifluoro-N-(2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-imidazol-2-yl)ethyl)methanesulfonamide

To a chilled solution of(E)-2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-imidazol-2-yl)ethanamine(29 mg, 0.057 mmol) in pyridine (0.5 ml) was addedtrifluoromethanesulfonic anhydride (0.048 ml, 0.284 mmol). It wasstirred at rt for 1.5 h and the mixture diluted with water and extractedwith EA twice. The aqueous layer was saturated with NH₄Cl and extractedwith EA twice more. The combined organic layers were dried over Na₂SO₄,filtered and concentrated. The crude was purified by ISCO using aRediSep® column (DCM-MeOH; 0-50%) to give 0.005 g of the title compound.¹H NMR (500 MHz, CDCl₃) δ ppm 1.21-1.32 (m, 2H) 1.60-1.70 (m, 2H)1.72-1.82 (m, 2H) 2.62 (t, J=7.41 Hz, 2H) 2.89 (t, J=5.83 Hz, 1H) 3.72(t, J=5.83 Hz, 1H) 3.84 (t, J=7.25 Hz, 2H) 5.04 (d, J=0.95 Hz, 2H) 6.85(s, 1H) 6.90-6.99 (m, 3H) 7.04 (d, J=16.39 Hz, 1H) 7.07-7.14 (m, 2H)7.58 (d, J=16.39 Hz, 1H) 7.61-7.69 (m, 5H) 7.69-7.73 (m, 1H). LRMS+H⁺:643.3.

Compound 56:(E)-1-(4-(4-((3-(4-(trifluoromethyl)styryl)benzyl)oxy)phenyl)butyl)-1H-1,2,3-triazole

Step 1: (3-methylbenzyl)triphenylphosphonium chloride

A mixture of 1-(chloromethyl)-3-methylbenzene (10 ml, 76 mmol) andtriphenylphosphine (22.82 g, 87 mmol) in xylene (106 ml, 288 mmol) washeated to reflux overnight. It was cooled to 20° C. and stirred for 1hour. The solids were collected on Buchner and the cake washed with0-xylene (4×25 mL) and dried at 20° C. under high vacuum until constantweight. This gave 28 g of the title compound. LRMS+367.1.

Step 2: (E)-1-methyl-3-(4-(trifluoromethyl)styryl)benzene

Potassium t-butoxide (2.198 g, 19.59 mmol) was added to(3-methylbenzyl)triphenylphosphonium chloride (7.52 g, 18.67 mmol) and4-(trifluoromethyl)benzaldehyde (2.5 mL, 18.31 mmol) in ethanol (21.91mL, 375 mmol). After 1 h, water (8.79 mL, 488 mmol) was added and theresulting white suspension was stirred for 30 minutes. The solids werecollected on Buchner and the cake washed with EtOH:water (7:4, 2×5 mL)and dried at 20° C. under high vacuum until constant weight.

This gave 2.52 g og the title compound. ¹H NMR (500 MHz, CDCl₃) δ ppm2.40 (s, 3H) 7.18 (d, J=16.43 Hz, 1H) 7.13 (d, J=7.04 Hz, 1H) 7.12 (d,J=16.43 Hz, 1H) 7.26-7.31 (m, 1H) 7.37 (s, 1H) 7.34 (s, 1H) 7.61 (s,4H).

Step 3: (E)-1-(bromomethyl)-3-(4-(trifluoromethyl)styryl)benzene

(E)-1-methyl-3-(4-(trifluoromethyl)styryl)benzene (1 g, 3.81 mmol) inCCl₄ (11.41 ml, 118 mmol) was heated to 70° C. for 30 minutes andN-bromosuccinimide (0.780 g, 4.38 mmol) and AIBN (0.063 g, 0.381 mmol)were added. After 6 hrs, cooled to 65° C. and filtered to remove thesuccinimide. The filtrate was concentrated and the residue purified onISCO using a RediSep® column (Hex/EtOAc; 0-30) to give 0.753 g of thetitle compound.

Step 4:(E)-1-(4-(4-((3-(4-(trifluoromethyl)styryl)benzyl)oxy)phenyl)butyl)-1H-1,2,3-triazole

4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenol and(E)-1-(bromomethyl)-3-(4-(trifluoromethyl)styryl)benzene gave the titlecompound following a procedure similar to compound 3. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.47 (quin, J=7.63 Hz, 2H) 1.80 (quin, J=7.34 Hz, 2H)2.52-2.56 (m, 2H) 4.38 (t, J=7.04 Hz, 2H) 5.09 (s, 2H) 6.94 (d, J=8.61Hz, 2H) 7.09 (d, J=8.61 Hz, 2H) 7.33-7.51 (m, 4H) 7.61 (d, J=7.43 Hz,1H) 7.67-7.76 (m, 4H) 7.83 (d, J=8.22 Hz, 2H) 8.10 (s, 1H). LRMS+H⁺:478.1.

Compound 57:(E)-1-(4-(4-((4-(4-(trifluoromethyl)styryl)benzyl)oxy)phenyl)butyl)-1H-1,2,3-triazole

Step 1: (4-methylbenzyl)triphenylphosphonium chloride

This compound was prepared in a similar fashion as the compound 56step 1. LRMS+367.1.

Step 2: (E)-1-methyl-4-(4-(trifluoromethyl)styryl)benzene

This compound was prepared in a similar fashion as the compound 56 step2 after a thermodynamic equilibrium with 3% iodine in refluxing toluene(0.2M) overnight. ¹H NMR (500 MHz, CDCl₃) δ ppm 2.38 (s, 3H) 7.08 (d,J=16.43 Hz, 1H) 7.18 (d, J=16.40 Hz, 1H) 7.20 (d, J=7.83 Hz, 2H) 7.44(d, J=8.22 Hz, 2H) 7.60 (s, 4H).

Step 3: (E)-1-(bromomethyl)-4-(4-(trifluoromethyl)styryl)benzene

This compound was prepared in a similar fashion as the compound 56 step3. ¹H NMR (500 MHz, CDCl₃) δ ppm 4.53 (s, 2H) 7.10-7.22 (m, 2H)7.39-7.45 (m, 2H) 7.52 (d, J=8.22 Hz, 2H) 7.58-7.64 (m, 4H).

Step 4:(E)-1-(4-(4-((4-(4-(trifluoromethyl)styryl)benzyl)oxy)phenyl)butyl)-1H-1,2,3-triazole

This compound was prepared in a similar fashion as the compound 56 step4. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.47 (quin, J=7.53 Hz, 2H) 1.80(quin, J=7.34 Hz, 2H) 2.52-2.56 (m, 2H) 4.38 (t, J=7.04 Hz, 2H) 5.08 (s,2H) 6.92 (d, J=8.61 Hz, 2H) 7.08 (d, J=8.61 Hz, 2H) 7.15 (s, 1H)7.32-7.50 (m, 4H) 7.63-7.76 (m, 4H) 7.79-7.86 (m, 2H) 8.11 (d, J=0.78Hz, 1H). LRMS+H⁺: 478.1.

Compound 58: (E)-methyl4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)benzoate

Step 1: (E)-3-(4-(methoxycarbonyl)phenyl)acrylic acid

A mixture of methyl 4-formylbenzoate (5 g, 30.5 mmol), malonic acid(4.75 g, 45.7 mmol) and piperidine (0.244 ml, 2.467 mmol) in pyridine(30.5 ml, 377 mmol) was heated to 85-90° C. After 3 hrs cooled to 20° C.and poured into HCl 2M in water (305 ml, 609 mmol). The resulting whitesuspension was cooled to 0° C. and stirred for 45 minutes. The solidswere collected on Buchner and the cake was washed with water (15 mL) andthen CH₃CN (2×15 mL). The product was dried at 20° C. under high vacuumuntil constant weight. This gave 5.94 g of the title product. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 3.86 (s, 3H) 6.66 (d, J=16.04 Hz, 1H) 7.64 (d,J=16.04 Hz, 1H) 7.84 (d, J=8.61 Hz, 2H) 7.97 (d, J=8.22 Hz, 2H) 12.58(s, 1H).

Step 2: (E)-methyl 4-(3-amino-3-oxoprop-1-en-1-yl)benzoate

This compound was prepared in a similar fashion as compound 3 step 1with the previous intermediate. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.86 (s,3H) 6.73 (d, J=16.04 Hz, 1H) 7.21 (br. s., 1H) 7.46 (d, J=16.04 Hz, 1H)7.61 (br. s., 1H) 7.70 (d, J=8.22 Hz, 2H) 7.98 (d, J=8.22 Hz, 2H).

Step 3: (E)-methyl 4-(2-(4-(chloromethyl)oxazol-2-yl)vinyl)benzoate

In a microwave vial were added (E)-methyl4-(3-amino-3-oxoprop-1-en-1-yl)benzoate (0.750 g, 3.65 mmol) and1,3-dichloropropan-2-one (0.557 g, 4.39 mmol) were heated at 130° C.After 1 hr, cooled to 20° C. and the resulting solid was dissolved inCH2Cl2 (10 mL) and filtered over glass wool to remove dark insolublesolid. After removal of the solvent the residue was purified on ISCOusing a RediSep® column (Hex/EtOAc; 0-50%) to gibe 0.258 g of the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.87 (s, 3H) 4.71 (s, 2H) 7.31(d, J=16.43 Hz, 1H) 7.60 (d, J=16.43 Hz, 1H) 7.88 (d, J=8.22 Hz, 2H)7.97 (d, J=8.22 Hz, 2H) 8.22 (s, 1H).

Step 4: (E)-methyl4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)benzoate

This compound was prepared in a similar fashion as the compound 32 step2 from (E)-methyl 4-(2-(4-(chloromethyl)oxazol-2-yl)vinyl)benzoate and4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenol. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.48 (quin, J=7.63 Hz, 2H) 1.81 (quin, J=7.34 Hz, 2H) 2.52-2.57 (m,2H) 3.86 (s, 3H) 4.39 (t, J=7.04 Hz, 2H) 4.98 (s, 2H) 6.94 (m, J=8.22Hz, 2H) 7.09 (m, J=8.61 Hz, 2H) 7.31 (d, J=16.43 Hz, 1H) 7.59 (d,J=16.43 Hz, 1H) 7.70 (s, 1H) 7.87 (d, J=8.22 Hz, 2H) 7.97 (d, J=8.22 Hz,2H) 8.11 (s, 1H) 8.23 (s, 1H). LRMS+H⁺: 459.1

Compound 59:(E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)—N-(prop-2-yn-1-yl)benzamide

Step 1:(E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)benzoicacid

NaOH 0.5M (0.654 μml, 0.327 μmmol) was added to (E)-methyl4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)benzoate(0.150 g, 0.327 mmol) in THE (1.5 ml). After 48 hrs, NaOH 0.5M in water(0.294 ml, 0.147 mmol) was added. After 68 hrs, HCl 0.5M in water (0.981ml, 0.491 mmol) was added and the resulting suspension was stirred for 1h. The solids were collected on Buchner and the cake was washed withwater (3×1 mL) and dried at 40° C. under high vacuum until constantweight. This gave 0.132 g of the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.48 (quin, J=7.63 Hz, 2H) 1.81 (quin, J=7.24 Hz, 2H)2.52-2.57 (m, 2H) 4.39 (t, J=7.04 Hz, 2H) 4.98 (s, 2H) 6.94 (d, J=8.61Hz, 2H) 7.09 (d, J=8.61 Hz, 2H) 7.30 (d, J=16.43 Hz, 1H) 7.59 (d,J=16.43 Hz, 1H) 7.70 (s, 1H) 7.84 (d, J=8.22 Hz, 2H) 7.95 (d, J=8.61 Hz,2H) 8.11 (s, 1H) 8.23 (s, 1H) 13.03 (br. s., 1H). LRMS+H⁺: 445.2.

Step 2:(E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)—N-(prop-2-yn-1-yl)benzamideyl)benzamide

EDC (19.41 mg, 0.101 mmol) was added to(E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)benzoicacid (30 mg, 0.067 mmol) and propargyl amine (10.81 μl, 0.169 mmol) inDMF (500 μl, 6.45 mmol) and let go overnight.

MeOH (500 μl, 12.35 mmol) and water (850 μl, 47.2 mmol) were added andthe resulting suspension stirred for 1 hour. The solids were collectedon Buchner and the cake was washed with water (3×0.5 mL) and dried at40° C. under high vacuum to give 0.022 g of the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.48 (quin, J=7.63 Hz, 2H) 1.81 (dt, J=14.97,7.19 Hz, 2H) 2.52-2.58 (m, 2H) 3.13 (t, J=2.54 Hz, 1H) 4.07 (dd, J=5.28,2.54 Hz, 2H) 4.39 (t, J=7.04 Hz, 2H) 4.98 (s, 2H) 6.94 (d, J=8.61 Hz,2H) 7.09 (d, J=8.61 Hz, 2H) 7.28 (d, J=16.43 Hz, 1H) 7.57 (d, J=16.43Hz, 1H) 7.70 (s, 1H) 7.82 (d, J=8.61 Hz, 2H) 7.89 (d, J=8.61 Hz, 2H)8.11 (s, 1H) 8.22 (s, 1H) 8.98 (t, J=5.48 Hz, 1H). LRMS+H⁺: 482.2.

Compound 60:(E)-(4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)phenyl)methanol

LiAlH₄ (9.1 mg, 0.24 mmol) was added to (E)-methyl4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)benzoate(0.050 g, 0.109 mmol) in THE (3.00 ml, 36.6 mmol) and the reactionstirred overnight. To the reaction mixture was added water (9 μL), NaOH3M (11.3 μL) and water (27 μL). After 15 minutes of stirring anhydrousMgSO₄ was added and stirred for 15 minutes. It was filtered and thesolvent removed. This gave 0.042 g of the title compound. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.48 (quin, J=7.60 Hz, 2H) 1.81 (quin, J=7.30 Hz,2H) 2.52-2.57 (m, 2H) 4.39 (t, J=7.04 Hz, 2H) 4.52 (d, J=5.48 Hz, 2H)4.96 (s, 2H) 5.24 (t, J=5.50 Hz, 1H) 6.94 (d, J=8.61 Hz, 2H) 7.06-7.16(m, 3H) 7.35 (d, J=7.83 Hz, 2H) 7.51 (d, J=16.43 Hz, 1H) 7.67 (d, J=8.22Hz, 2H) 7.70 (s, 1H) 8.11 (s, 1H) 8.17 (s, 1H). LRMS+H⁺: 431.2.

Compound 61:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-methoxystyryl)oxazole

Step 1: (E)-3-(2-fluoro-4-methoxyphenyl)acrylic acid

This compound was prepared in a similar fashion as compound 58 step 1with 2-fluoro-4-(trifluoromethoxy)benzaldehyde. LRMS-H⁺: 249.1

Step 2: (E)-3-(2-fluoro-4-methoxyphenyl)acrylamide

This compound was in a similar fashion as compound 3 step 1 with theprevious intermediate. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.80 (s, 3H) 6.56(d, J=16.04 Hz, 1H) 6.84 (dd, J=8.61, 2.74 Hz, 1H) 6.91 (dd, J=12.91,2.35 Hz, 1H) 7.08 (br. s., 1H) 7.41 (d, J=16.04 Hz, 1H) 7.50-7.60 (m,2H).

Step 3: (E)-4-(chloromethyl)-2-(2-fluoro-4-methoxystyryl)oxazole

(E)-3-(2-fluoro-4-methoxyphenyl)acrylamide (0.250 g, 1.281 mmol) and1,3-dichloropropan-2-one (0.195 g, 1.537 mmol) were heated to 130° C.for 1 hr. Cooled to 20° C. and the resulting black solid was dissolvedin CH₂Cl₂ (4 mL) and filtered over glass wool to remove the darkinsoluble solid. Concentrated to dryness and the residue was purified onISCO using a RediSep® column (Hex/EtOAc; 0-50%) to give 89 mg of thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.82 (s, 3H) 4.69 (s,2H) 6.86 (dd, J=8.61, 2.35 Hz, 1H) 6.93 (dd, J=13.11, 2.54 Hz, 1H) 7.06(d, J=16.43 Hz, 1H) 7.51 (d, J=16.43 Hz, 1H) 7.83 (t, J=9.00 Hz, 1H)8.15 (s, 1H).

Step 4:(E)-4-((4-4-1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-methoxystyryl)oxazole

(E)-4-(chloromethyl)-2-(2-fluoro-4-methoxystyryl)oxazole (30 mg, 0.112mmol), 4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenol (26.8 mg, 0.123 mmol)and K₂CO₃ (17.04 mg, 0.123 mmol) in DMF (183 μl, 2.360 mmol) were heatedto 75° C. for 5 hrs. It was cooled to 20° C. and MeOH (183 μl, 4.52mmol) and water (305 μl, 16.90 mmol) were added. The mixture was stirredovernight. The solids were collected on Buchner and the cake was washedwith water (3×0.5 mL) and dried at 40° C. to give 0.042 g of the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48 (quin, J=7.63 Hz, 2H)1.81 (quin, J=7.34 Hz, 2H) 2.52-2.56 (m, 2H) 3.82 (s, 3H) 4.39 (t,J=7.04 Hz, 2H) 4.96 (s, 2H) 6.81-6.97 (m, 4H) 7.02-7.12 (m, 3H) 7.50 (d,J=16.82 Hz, 1H) 7.70 (s, 1H) 7.82 (t, J=9.00 Hz, 1H) 8.11 (s, 1H) 8.17(s, 1H). LRMS+H⁺: 449.2.

Compound 62:(E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)phenol

A mixture of(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-methoxystyryl)oxazole(50 mg, 0.116 mmol) in HBr 48% wt in water (201 μl, 1.777 mmol) washeated to 90° C. After 2 hrs water (1 mL) and MeOH (1 mL) were added andextracted the mixture with CH₂Cl₂ (3×2 mL). The organic phases werecombined and the solvent removed. The residue was purified on ISCO usinga RediSep® column (CH₂Cl₂/MeOH; 0-100%). The solid thus obtained wassuspended in CH₃CN (0.5 mL) and heated to reflux for 15 minutes. It wascooled to 20° C. and stirred for 1 hour. The solids were collected onBuchner and the cake was washed with CH₃CN (2×0.15 mL) and dried at 40°C. under high vacuum. This gave 0.006 g of the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.48 (quin, J=7.70 Hz, 2H) 1.81 (quin, J=7.34Hz, 2H) 2.52-2.56 (m, 2H) 4.39 (t, J=7.04 Hz, 2H) 4.94 (s, 2H) 6.79 (m,J=8.61 Hz, 2H) 6.85-6.97 (m, 3H) 7.09 (m, J=8.61 Hz, 2H) 7.42 (d,J=16.43 Hz, 1H) 7.54 (d, J=8.61 Hz, 2H) 7.70 (s, 1H) 8.11 (s, 1H) 8.11(s, 1H) 9.85 (s, 1H). LRMS+H⁺: 417.1.

Compound 63:(E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)benzamide

(E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)benzonitrile(50 mg, 0.118 mmol) in EtOH (1777 μl, 30.4 mmol) and DMF (901 μl, 11.63mmol) was heated to 50° C. for 5 minutes to obtain a solution. NaOH 3Min water (96 μl, 0.288 mmol) and hydrogen peroxide 30% wt. in water(48.0 μl, 0.470 mmol) were then added. After 3 hours then cooled to 20°C. and continued stirring. Water (900 μl, 49.9 mmol) was added thesuspension was stirred for 1 hour. The solids were then collected onBuchner and the cake was washed with water (3×0.5 mL) and dried at 40°C. under high vacuum until. This gave 0.044 g of the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.48 (quin, J=7.63 Hz, 2H) 1.81 (quin,J=7.34 Hz, 2H) 2.52-2.57 (m, 2H) 4.39 (t, J=7.04 Hz, 2H) 4.98 (s, 2H)6.94 (d, J=8.61 Hz, 2H) 7.09 (d, J=8.22 Hz, 2H) 7.27 (d, J=16.43 Hz, 1H)7.41 (br. s., 1H) 7.57 (d, J=16.43 Hz, 1H) 7.70 (s, 1H) 7.80 (d, J=8.61Hz, 2H) 7.90 (d, J=8.22 Hz, 2H) 8.02 (br. s., 1H) 8.11 (s, 1H) 8.21 (s,1H).

Compound 64:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-ethynylstyryl)oxazole

To a N₂ flush vial containing(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-bromostyryl)oxazole(75 mg, 0.156 mmol), copper (I) iodide (2.9 mg, 0.016 mmol) and(Ph₃P)₂PdCl₂ (10.98 mg, 0.016 mmol) was added DMF (608 μl, 7.85 mmol),triethylamine (607 μl, 4.36 mmol) and trimethylsilylacetylene (110 μl,0.782 mmol). The reaction was heated to 60° C. overnight and filteredover 0.45 μm filter and the solvent removed. The residue was dissolvedin THE (3000 μl, 36.6 mmol) and cooled to 0° C. TBAF 1M in THE (203 μl,0.203 mmol) was added and 30 minutes later, CH₂Cl₂ (20 mL) was added.This was washed with water (20 mL) and the organic layer dried overMgSO₄, filtered and concentrated. The residue was purified on ISCO usinga RediSep® column (CH₂Cl₂/MeOH; 0-10%) to give 0.024 g of ta solid thatwas suspended in CH₃CN (0.5 mL) and heated to reflux for 15 minutes.Cooled to 20° C. and stirred for 30 minutes. The solids were collectedon Buchner and the cake was washed with CH₃CN (1×0.5 mL) and dried at40° C. under high vacuum to give 0.0045 g of the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.48 (quin, J=7.70 Hz, 2H) 1.81 (quin, J=7.34Hz, 2H) 2.52-2.58 (m, 2H) 4.39 (t, J=7.04 Hz, 2H) 4.97 (d, J=2.35 Hz,2H) 6.94 (d, J=8.61 Hz, 2H) 7.09 (d, J=8.22 Hz, 2H) 7.21 (d, J=16.43 Hz,1H) 7.27 (d, J=16.43 Hz, 1H) 7.46-7.61 (m, 2H) 7.65 (d, J=8.22 Hz, 1H)7.70 (s, 1H) 7.74 (d, J=8.22 Hz, 1H) 7.80 (d, J=8.22 Hz, 1H) 8.11 (s,1H) 8.21 (d, J=6.26 Hz, 1H).

Compound 65:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-nitrostyryl)oxazole

A mixture of (E)-4-(chloromethyl)-2-(2-fluoro-4-nitrostyryl)oxazole(0.118 g, 0.418 mmol), 4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenol (0.100g, 0.460 mmol) and K₂CO₃ (0.069 g, 0.502 mmol) was heated in DMF (0.837ml) at 75° C. overnight. The temperature was brought to 50° C. and MeOH(0.677 ml, 16.74 mmol) was added followed by water (1.131 ml, 62.8mmol). The temperature was brought to rt and the mixture filtered andabsorbed on SiO₂ and purified on ISCO using a RediSep® column (DCM-MeOH;0-10%) to give 0.099 g of the title compound. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.48 (quin, J=7.60 Hz, 2H) 1.81 (quin, J=7.60 Hz, 2H) 2.53 (t,J=7.60 Hz, 2H) 4.39 (t, J=7.04 Hz, 2H) 5.00 (s, 2H) 6.94 (2, J=8.61 Hz,2H) 7.10 (2, J=8.61 Hz, 2H) 7.47 (d, J=16.82 Hz, 1H) 7.61 (d, J=16.82Hz, 1H) 7.70 (s, 1H) 8.09-8.15 (m, 2H) 8.17-8.26 (m, 2H) 8.29 (s, 1H).

Compound 66:(E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)-3-fluoroaniline

To a mixture of(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-nitrostyryl)oxazole(0.096 g, 0.207 mmol) in THE (3.0 ml)-EtOAc (4.0 ml) was added SnCl₂·H₂O(0.234 g, 1.036 mmol) and it was heated to 75° C. for 5 h. After aquenched with a solution of NaHCO₃ sol, it was diluted with EA, filteredon celite and the organic phase separated. The aqueous was extractedwith EA and the combined organic phases washed with brine and dried overNa₂SO₄ dried. After filtration the solvent was removed. This gave 0.069g of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48 (quin,J=7.63 Hz, 2H) 1.81 (quin, J=7.34 Hz, 2H) 2.52-2.56 (m, 2H) 4.39 (t,J=7.04 Hz, 2H) 4.93 (s,2H) 5.95 (s, 2H) 6.34 (dd, J=13.89, 2.15 Hz, 1H)6.42 (dd, J=8.61, 1.96 Hz, 1H) 6.79 (d, J=16.43 Hz, 1H) 6.93 (d, J=8.61Hz, 2H) 7.09 (d, J=8.61 Hz, 2H) 7.40 (d, J=16.43 Hz, 1H) 7.49 (t, J=8.80Hz, 1H) 7.70 (s, 1H) 8.10 (d, J=8.22 Hz, 2H).

Compound 67:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-azido-2-fluorostyryl)oxazole

To a 0° C. suspension of(E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)-3-fluoroaniline(0.068 g, 0.157 mmol) in acetonitrile (1.05 ml) was added tert-butylnitrite (0.026 ml, 0.220 mmol) followed by trimethylsilyl azide (0.025ml, 0.188 mmol). This was brought to rt and after 3 h the solvent wasremoved. Purification on ISCO using a RediSep® column (DCM-MeOH) gave0.039 g of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48(quin, J=7.63 Hz, 2H) 1.81 (quin, J=7.60 Hz, 2H) 2.52-2.57 (m, 2H) 4.39(t, J=7.04 Hz, 2H) 4.97 (s, 2H) 6.93 (d, J=8.61 Hz, 2H) 7.05 (dd,J=8.22, 2.35 Hz, 1H) 7.09 (d, J=8.61 Hz, 2H) 7.12-7.24 (m, 2H) 7.52 (d,J=16.43 Hz, 1H) 7.70 (s, 1H) 7.95 (t, J=8.61 Hz, 1H) 8.11 (s, 1H) 8.20(s, 1H).

Compound 68:(E)-2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethyldimethylcarbamate

Dimethylcarbamic chloride (5.43 μl, 0.059 mmol) was added to compound 4(0.020 g, 0.039 mmol) in pyridine (0.013 ml) and brought to 100° C. for10 h. It was then diluted with EA and quenched with a CuSO₄ solution.The phases were separated and the aqueous extracted 2× with EA. Theywere combined, Na₂SO₄ dried, filtered and purified on preparative HPLC(35-100% MeOH(5% HCO₂H)-water(5% HCO₂H) to give 0.007 g of the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.47 (quin, J=7.53 Hz, 2H)1.78 (quin, J=7.60 Hz, 2H) 2.51-2.56 (m, 2H) 2.76 (br. s., 6H) 2.91 (t,J=6.65 Hz, 2H) 4.17 (t, J=6.65 Hz, 2H) 4.33 (t, J=7.04 Hz, 2H) 4.98 (s,2H) 6.94 (d, J=8.61 Hz, 2H) 7.09 (d, J=8.61 Hz, 2H) 7.34 (d, J=16.43 Hz,1H) 7.61 (d, J=16.43 Hz, 1H) 7.76 (d, J=8.22 Hz, 2H) 7.89 (s, 1H) 7.95(d, J=7.83 Hz, 2H) 8.24 (s, 1H).

Compound 69:(E)-2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethyl(2-methoxyethyl)carbamate

1-isocyanato-2-methoxyethane (7.89 mg, 0.078 mmol) was added to asuspension of compound 4 (0.020 g, 0.039 mmol) and Hunig'sBase (0.014ml, 0.078 mmol) in DCM (0.098 ml) at rt. After 3 h the solvent wasremoved and the residue absorbed on SiO₂. Purification on ISCO using aRediSep® column (Hx-EA; 20-100%) gave 0.017 g of the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.49 (quin, J=7.20 Hz, 2H) 1.79 (quin,J=7.24 Hz, 2H) 2.52-2.57 (m, 2H) 2.89 (t, J=6.85 Hz, 2H) 3.07-3.15 (m,2H) 3.21 (s, 3H) 3.27-3.31 (m, 2H) 4.16 (t, J=6.85 Hz, 2H) 4.32 (t,J=6.85 Hz, 2H) 4.98 (s, 2H) 6.94 (d, J=8.61 Hz, 2H) 7.10 (d, J=8.22 Hz,2H) 7.15 (t, J=5.67 Hz, 1H) 7.34 (d, J=16.43 Hz, 1H) 7.62 (d, J=16.43Hz, 1H) 7.76 (d, J=8.22 Hz, 2H) 7.90 (s, 1H) 7.95 (d, J=8.22 Hz, 2H)8.23 (s, 1H).

Compound 70:(E)-2-(1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethylisopropylcarbamate

This compound was prepared in a similar fashion as compound 69 with2-isocyanatopropane. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (d, J=6.26 Hz,6H) 1.49 (quin, J=7.40 Hz, 2H) 1.78 (quin, J=7.24 Hz, 2H) 2.51-2.56 (m,2H) 2.89 (t, J=6.65 Hz, 2H) 3.48-3.63 (m, 1H) 4.15 (t, J=6.85 Hz, 2H)4.32 (t, J=7.04 Hz, 2H) 4.98 (s, 2H) 6.94 (d, J=8.22 Hz, 2H) 7.01 (d,J=7.04 Hz, 1H) 7.10 (d, J=8.61 Hz, 2H) 7.34 (d, J=16.83 Hz, 1H) 7.62 (d,J=16.43 Hz, 1H) 7.76 (d, J=8.61 Hz, 2H) 7.89 (s, 1H) 7.95 (d, J=8.22 Hz,2H) 8.24 (s, 1H).

Compound 71:(E)-4-((1-(4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)methyl)thiomorpholine1,1-dioxide

Step 1:(E)-4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butan-1-ol

A mixture of(E)-4-(chloromethyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole(1.159 g, 3.79 mmol), K₂CO₃ (0.786 g, 5.69 mmol) and4-(4-hydroxybutyl)phenol (0.63 g, 3.79 mmol) in DMF (12 ml) was heatedovernight at 75° C. The solvent removed and the residue was purified onISCO using a RediSep® column (Hx-EA; 20-100%) to give 1.00 g of thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42 (s, 2H) 1.49-1.61(m, 2H) 3.39 (q, J=5.50 Hz, 2H) 4.35 (t, J=5.28 Hz, 1H) 4.99 (s, 2H)6.94 (d, J=8.61 Hz, 2H) 7.11 (d, J=8.22 Hz, 2H) 7.39 (d, J=16.43 Hz, 1H)7.59 (d, J=16.82 Hz, 1H) 7.64 (d, J=8.22 Hz, 1H) 7.77 (s, 1H) 8.16 (t,J=7.83 Hz, 1H) 8.26 (s, 1H).

Step 2:(E)-4-((4-(4-azidobutyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

This compound was prepared in a similar fashion as compound 1 step 2with(E)-4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butan-1-ol,method B. LRMS+H⁺: 461.0.

Step 3:(E)-4-((1-(4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)methyl)thiomorpholine1,1-dioxide

This compound was prepared in a similar way as compound 12 step 1 withthe previous intermediate and 4-(prop-2-yn-1-yl)thiomorpholine1,1-dioxide. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48 (quin, J=7.20 Hz, 2H)1.80 (quin, J=7.24 Hz, 2H) 2.51-2.57 (m, 2H) 2.89 (br. s., 4H) 3.09 (br.s., 4H) 3.76 (br. s., 2H) 4.36 (t, J=7.04 Hz, 2H) 4.99 (s, 2H) 6.94 (d,J=8.22 Hz, 2H) 7.09 (d, J=8.61 Hz, 2H) 7.39 (d, J=16.43 Hz, 1H) 7.59 (d,J=16.43 Hz, 1H) 8.02 (s, 1H) 8.16 (s, 1H) 8.26 (s, 1H).

Compound 72:(E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)-N-(2-(5-(dimethylamino)naphthalene-1-sulfonamido)ethyl)benzamide

Step 1: N-(2-aminoethyl)-5-(dimethylamino)naphthalene-1-sulfonamide

In a 100 mL round-bottomed flask was added ethylenediamine (2.503 ml,37.1 mmol) in CH₂Cl₂ (13.75 ml) to give a colorless solution. Cooled to0° C. A solution of 5-(dimethylamino)naphthalene-1-sulfonyl chloride(0.5 g, 1.854 mmol) in CH₂Cl₂ (15.00 ml) was added dropwise over 45minutes. Warmed to 20° C. and stirred o/n. After 22 hrs, HCl 2M in water(46.3 ml, 93 mmol) was added and stirred vigorously for 10 minutes.Separated layers. The aqueous layer was washed with CH₂Cl₂ (10 mL).Basified the aqueous layer to pH 9 with KOH 45% wt. in water (5.00 ml,58.4 mmol). Extracted the aqueous layer with CH₂Cl₂ (2×15 mL). Thecombined organic layers was dried over MgSO4, filtered and concentratedto dryness to giveN-(2-aminoethyl)-5-(dimethylamino)naphthalene-1-sulfonamide (457 mg,1.558 mmol, 84% yield) as a yellow foam. ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.47 (m, J=6.30 Hz, 2H) 2.77 (m, J=12.90, 6.30 Hz, 2H) 2.83 (s, 6H) 3.35(br. s., 2H) 7.26 (d, J=7.43 Hz, 1H) 7.36 (s, 1H) 7.55-7.67 (m, 2H)8.06-8.13 (m, 1H) 8.30 (d, J=8.61 Hz, 1H) 8.46 (d, J=8.61 Hz, 1H).

Step 2:(E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)-N-(2-(5-(dimethylamino)naphthalene-1-sulfonamido)ethyl)benzamide

This compound was prepared in a similar fashion as the compound 59 step2 using(E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)benzoicacid and the previous amine. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48 (quin,J=7.50 Hz, 2H) 1.81 (quin, J=7.50 Hz, 2H) 2.52-2.58 (m, 2H) 2.81 (s, 6H)2.95 (q, J=6.52 Hz, 2H) 3.22-3.31 (m, 2H) 4.39 (t, J=7.04 Hz, 2H) 4.97(s, 2H) 6.94 (m, J=8.61 Hz, 2H) 7.09 (m, J=8.61 Hz, 2H) 7.20-7.32 (m,2H) 7.51-7.65 (m, 3H) 7.70 (s, 1H) 7.73-7.81 (m, 4H) 8.03-8.14 (m, 3H)8.21 (s, 1H) 8.28 (d, J=8.61 Hz, 1H) 8.39-8.49 (m, 2H).

Compound 73:4-((4-(41H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(5-fluoro-1H-indol-2-yl)oxazole

This compound was prepared as described in Example 3 (page 18) of USpatent application publication no. 2006/0063812. LRMS+H⁺: 432.1.

Compound 74:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)oxazole

In a 5 mL round-bottomed flask was added NaH 60% wt. in mineral oil(8.53 mg, 0.213 mmol) in DMSO (500 μl) to give a grey suspension.Trimethylsulfoxonium iodide (46.9 mg, 0.213 mmol) was added in oneportion. The reaction mixture was stirred at 20° C. for 30 μminutes.(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-(trifluoro-methyl)styryl)oxazole(42.5 mg, 0.091 mmol) was added. Heated to 35° C. for 22 hours. In a 5mL vial was added NaH 60% wt. in mineral oil (8.53 mg, 0.213 mmol) inDMSO (500 μl) to give a gray suspension. Trimethylsulfoxonium iodide(100 mg, 0.454 mmol) was added. Stirred for 30 minutes. Added the ylidemixture to the reaction flask and rinsed vial with DMSO (500 μl).Continued stirring at 35° C. for 12 days. Poured the reaction mixture inWater (5 mL) and rinsed flask with MeOH (1.5 mL) and added to theresulting suspension. Stirred the suspension o/n. The mixture wasextracted with CH₂Cl₂ (2×5 mL). The combined organic layers were washedwith water (10 mL). The organic layer was dried over MgSO₄, filtered andconcentrated and the residue was purified on ISCO using a RediSep®column (Hex-EtOAc; 0-100%) to give(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)oxazole (8 mg, 0.017 mmol, 18.28% yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.22 (s, 1H), 8.11 (s, 1H), 7.86 (d, J=8.2 Hz, 2H),7.77 (d, J=8.6 Hz, 2H), 7.70 (s, 1H), 7.07-7.13 (m, J=8.6 Hz, 2H),6.91-6.99 (m, J=8.6 Hz, 2H), 6.82 (s, 1H), 5.01 (s, 2H), 4.39 (t, J=7.0Hz, 2H), 2.61-2.69 (m, 2H), 2.52-2.58 (m, 3H), 1.81 (quin, J=7.2 Hz,2H), 1.40-1.54 (m, 2H).

Compound 75:5-(4(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-(trifluoromethyl)phenyl)pyridine

Step 1: Methyl 6-(4-(trifluoromethyl)phenyl)nicotinate

In a 200 mL round-bottomed flask were added methyl 6-chloronicotinate (2g, 11.66 mmol) and (4-(trifluoromethyl)phenyl)boronic acid (2.435 g,12.82 mmol) in dioxane (43.7 ml) to give a tan solution. Cesium fluoride(6.20 g, 40.8 mmol) was added. Nitrogen was bubbled in the flask for 5minutes. Pd(dppf)Cl₂·DCM (0.286 g, 0.350 mmol) was added. Nitrogen wasbubbled in the flask for 5 minutes. Heated to 100° C. for 2 days.Diluted the reaction mixture with EtOAc (50 mL). Filtered the mixtureover celite and rinsed with EtOAc (2×25 mL). Concentrated to dryness andthe residue was purified on ISCO using a RediSep® Gold column(Hex-EtOAc; 0-40%) to give 2.35 g of the title compound. ¹H NMR (400MHz, DMSO-d₆) δ ppm 9.21 (d, J=2.0 Hz, 1H), 8.34-8.46 (m, 3H), 8.25 (d,J=8.6 Hz, 1H), 7.90 (d, J=8.2 Hz, 2H), 3.92 (s, 3H).

Step 2: (6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methanol

To a 0-5° C. solution of methyl 6-(4-(trifluoromethyl)phenyl) nicotinate(2.35 g, 8.36 mmol) in THE (25.7 ml) was added LiAlH₄ (0.327 g, 8.61mmol. It was stirred at 0° C. for 1 hour and diluted with Et₂O (75 mL).Water (0.327 ml) was then added slowly followed by NaOH 15% wt. in water(0.327 ml) then by water (0.980 ml). Warmed to 20° C. and stirred for 15minutes. Added anhydrous MgSO₄ and stirred for 15 minutes. Filtered themixture to remove the salts and rinsed with Et₂O (3×15 mL). Concentratedto dryness to give 2.05 g of the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.66 (d, J=2.0 Hz, 1H), 8.30 (d, J=8.2 Hz, 2H), 8.05 (d,J=7.8 Hz, 1H), 7.80-7.90 (m, 3H), 5.39 (t, J=5.8 Hz, 1H), 4.60 (d, J=5.8Hz, 2H).

Step 3: 5-(chloromethyl)-2-(4-(trifluoromethyl)phenyl)pyridine

In a 100 mL round-bottomed flask was added(6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methanol (1 g, 3.95 mmol) inCH₂Cl₂ (19 ml). Cooled to 0° C. and SOCl₂ (0.576 ml, 7.90 mmol) wasadded dropwise. Stirred at 0° C. for 5 minutes then warmed to 20° C.After 30 minutes, poured reaction mixture into ice+sat. NaHCO₃ (10 g+30mL). Stirred for 5 minutes. Extracted with EtOAc (2×30 mL). The combinedorganic layers were washed with water (30 mL) then brine (25 mL). Theorganic layer was dried over MgSO₄, filtered and concentrated to give1.07 g of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.79 (d,J=2.3 Hz, 1H), 8.29-8.35 (m, J=8.2 Hz, 2H), 8.12 (d, J=8.2 Hz, 1H), 8.02(dd, J=8.2, 2.3 Hz, 1H), 7.83-7.90 (m, J=8.2 Hz, 2H), 4.90 (s, 2H).

Step 4:5-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-(trifluoromethyl)phenyl)pyridine

This compound was prepared according to compound 1 step 5. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.79 (d, J=1.6 Hz, 1H), 8.28-8.36 (m, J=8.2 Hz, 2H),8.08-8.14 (m, 2H), 8.00 (dd, J=8.2, 2.0 Hz, 1H), 7.83-7.89 (m, J=8.2 Hz,2H), 7.70 (s, 1H), 7.06-7.14 (m, J=8.6 Hz, 2H), 6.92-6.99 (m, J=8.6 Hz,2H), 5.18 (s, 2H), 4.39 (t, J=7.0 Hz, 2H), 2.52-2.58 (m, 2H), 1.80(quin, J=7.3 Hz, 2H), 1.48 (quin, J=7.6 Hz, 2H).

Compound 76:4-((4(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(4-(trifluoromethyl)phenyl)cyclopropyl)oxazole

Step 1: (E)-ethyl 3-(4-(trifluoromethyl)phenyl)acrylate

In a 100 mL round-bottomed flask were added(E)-3-(4-(trifluoromethyl)phenyl)acrylic acid (2 g, 9.25 mmol) andsulfuric acid (0.200 ml, 3.75 mmol) in anhydrous ethanol (20.00 ml) togive a white suspension. Heated to reflux and stirred 19 hours.Concentrated the reaction mixture to dryness. The residue wasneutralized with sat. NaHCO₃ (15 mL). Extracted with EtOAc (3×15 mL).The combined organic layers were washed with brine (15 mL). The organiclayer was dried over MgSO₄, filtered and concentrated to give (E)-ethyl3-(4-(trifluoromethyl)phenyl)acrylate (2.20 g, 9.01 mmol, 97% yield) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.95 (d, J=8.2 Hz, 2H),7.77 (d, J=8.2 Hz, 2H), 7.72 (d, J=16.0 Hz, 1H), 6.79 (d, J=16.0 Hz,1H), 4.21 (q, J=7.0 Hz, 2H), 1.27 (t, J=7.0 Hz, 3H).

Step 2: Ethyl 2-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylate

In a 100 mL round-bottomed flask was added NaH 60% wt. in mineral oil(0.649 g, 16.22 mmol) in DMSO (22 ml) to give a grey suspension.Trimethylsulfoxonium iodide (3.57 g, 16.22 mmol) was added in portions.Stirred for 30 minutes. A solution of (E)-ethyl3-(4-(trifluoromethyl)phenyl)acrylate (2.2 g, 9.01 mmol) in DMSO (9 ml)and THE (9 ml) was added. Stirred at 20° C. for 19 hours. The reactionmixture was quenched with HCl 1M (10 mL). The mixture was extracted withEtOAc (2×20 mL). The combined organic layers were washed with water(3×20 mL) then with Brine (20 mL). The organic layer was dried overMgSO₄, filtered and concentrated to give 1.8 g as an orange oil. Theresidue was purified on ISCO using a RediSep® column (Hexane-Et₂O;0-50%) to give 0.703 g of the title compound. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 7.57-7.66 (m, J=8.2 Hz, 2H), 7.37-7.45 (m, J=7.8 Hz, 2H), 4.11 (q,J=7.3 Hz, 2H), 2.51-2.59 (m, 1H), 2.00-2.09 (m, 1H), 1.52 (dt, J=9.5,4.8 Hz, 1H), 1.41-1.49 (m, 1H), 1.20 (t, J=7.2 Hz, 3H).

Step 3: 2-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid

In a 50 mL round-bottomed flask was added ethyl2-(4-(trifluoromethyl)phenyl) cyclopropanecarboxylate (0.700 g, 2.71mmol) in ethanol (7 ml) to give a colorless solution. NaOH 1M in water(7.00 ml, 7.00 mmol) was added. The resulting mixture was stirred at 20°C. for 1.5 hour. Concentrated to ca. 5 mL on rotovap. Acidified to pH 3with HCl 2M in water (2.60 ml, 5.20 mmol). Extracted the aqueous layerwith EtOAc (2×15 mL). The combined organic layers were washed with Brine(15 mL). The organic layer was dried over MgSO₄, filtered andconcentrated to give 2-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylic acid (582 mg, 2.53 mmol, 93% yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm 12.42 (br. s., 1H), 7.58-7.65 (m, J=8.2 Hz, 2H),7.36-7.44 (m, J=8.2 Hz, 2H), 2.52-2.54 (m, 1H), 1.87-1.96 (m, 1H), 1.49(dt, J=9.2, 4.8 Hz, 1H), 1.41 (ddd, J=8.4, 6.3, 4.5 Hz, 1H).

Step 4: 2-(4-(trifluoromethyl)phenyl)cyclopropanecarboxamide

In a 100 mL round-bottomed flask were added2-(4-(trifluoromethyl)phenyl) cyclopropanecarboxylic acid (0.58 g, 2.52mmol) and DMF (9.76 μl, 0.126 mmol) in CH₂Cl₂ (16 ml) to give a lightyellow solution. Cooled to 0° C. Oxalyl chloride (0.287 ml, 3.28 mmol)was added slowly. Warmed to 20° C. and stirred for 1 hour. Concentratedthe reaction mixture to dryness. The resulting residue was dissolved inCH₂Cl₂ (13 ml) and cooled to 0° C. NH₄OH_(conc) (0.851 ml, 12.60 mmol)was added. After 30 minutes, concentrated to dryness on rotovap. Theresulting solid was suspended in EtOH (6 mL) and heated to reflux toobtain a solution. Added slowly water (6 mL). The resulting slurry wascooled to 20° C. Water (6 mL) was added and stirred the resultingsuspension for 1 hour. The solids were collected on Buchner and the cakewas washed with water (3×3 mL). Dried the product at 20° C. under highvacuum until constant weight to give 2-(4-(trifluoromethyl)phenyl)cyclopropanecarboxamide (525 mg, 2.291 mmol, 91% yield). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 7.62 (d, J=8.2 Hz, 3H), 7.35 (d, J=8.2 Hz, 2H),6.95 (br. s., 1H), 2.26-2.37 (m, 1H), 1.86-1.96 (m, 1H), 1.39 (dt,J=9.1, 4.6 Hz, 1H), 1.28 (ddd, J=8.3, 5.8, 4.3 Hz, 1H).

Step 5:4-(chloromethyl)-2-(2-(4-(trifluoromethyl)phenyl)cyclopropyl)oxazole

In a 15 mL sealed tube were added 2-(4-(trifluoromethyl)phenyl)cyclopropanecarboxamide (0.250 g, 1.091 mmol) and1,3-dichloropropan-2-one (0.208 g, 1.636 mmol) in toluene (1.5 ml) andDMF (0.3 ml) to give a tan solution. Sealed the vial and heated to 120°C. for 22 hours. Cooled the mixture to 20° C., added CH₂Cl₂ (5 mL) andstirred for 15 minutes. Filtered over glass wool in pipet to remove darkunsoluble solid. Concentrated to dryness. The residue was purified onISCO using a RediSep® column (Hex-EtOA: 0-50%) to give4-(chloromethyl)-2-(2-(4-(trifluoromethyl)phenyl) cyclopropyl)oxazole(187 mg, 0.620 mmol, 56.8% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.04(s, 1H), 7.60-7.68 (m, J=8.2 Hz, 2H), 7.43-7.49 (m, J=8.2 Hz, 2H), 4.62(s, 2H), 2.59-2.69 (m, 1H), 2.52-2.59 (m, 1H), 1.66-1.73 (m, 1H), 1.63(dt, J=8.9, 5.5 Hz, 1H).

Step 6:4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(4-(trifluoromethyl)phenyl)cyclopropyl)oxazole

This compound was prepared according to compound 1 step 5. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.24 (s, 1H), 8.11 (s, 1H), 7.91-8.00 (m, J=8.2 Hz,2H), 7.73-7.81 (m, J=8.2 Hz, 2H), 7.70 (s, 1H), 7.62 (d, J=16.4 Hz, 1H),7.34 (d, J=16.4 Hz, 1H), 7.05-7.13 (m, J=8.2 Hz, 2H), 6.90-6.98 (m,J=8.6 Hz, 2H), 4.98 (s, 2H), 4.39 (t, J=7.0 Hz, 2H), 2.52-2.57 (m, 2H),1.81 (quin, J=7.3 Hz, 2H), 1.48 (quin, J=7.6 Hz, 2H).

Compound 77: Methyl2-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazole-4-carboxylate

Step 1: Methyl 2-(dichloromethyl)-4,5-dihydrooxazole-4-carboxylate

In a 200 mL round-bottomed flask was added sodium methoxide 30% wt. inMeOH (1.690 ml, 9.10 mmol) in MeOH (18 ml) to give a colorless solution.Cooled to −10° C. 2,2-dichloroacetonitrile (7.30 ml, 91 mmol) was addeddropwise over 15 minutes. Continued stirring at that temperature for 20minutes. A suspension of methyl 2-amino-3-hydroxypropanoatehydrochloride (14.15 g, 91 mmol) in MeOH (15 ml) was added to thereaction mixture. Slowly warmed to 20° C. and stirred for 19.5 hours.CH₂Cl₂ (51 ml) and water (29 ml) were added. Stirred vigorously for 5minutes. Separated layers. The organic layer was concentrated to drynesson rotovap. The aqueous layer was extracted 2 times with CH₂Cl₂ (29 ml).The combined extracts were added to the concentrated 1st organic layer.The organic layer was dried over MgSO₄, filtered and concentrated todryness to give methyl2-(dichloromethyl)-4,5-dihydrooxazole-4-carboxylate (17.64 g, 83 mmol,91% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 6.29 (s, 1H), 4.85-4.96 (m,1H), 4.76 (t, J=8.6 Hz, 1H), 4.61-4.72 (m, 1H), 3.83 (s, 3H).

Step 2: Methyl2-(chloromethyl)-4-methoxy-4,5-dihydrooxazole-4-carboxylate

In a 200 mL round-bottomed flask was added methyl2-(dichloromethyl)-4,5-dihydrooxazole-4-carboxylate (17.64 g, 83 mmol)in MeOH (19 ml) to give an orange solution. Cooled to 0° C. Sodiummethoxide 30% wt. in methanol (15.46 ml, 83 mmol) was added dropwiseover 50 minutes. Slowly warmed the resulting light orange suspension to20° C. and stirred for 18 hours. CH₂Cl₂ (54 ml) and water (30 ml) wereadded. Stirred vigorously for 5 minutes. Separated layers. The organiclayer was concentrated to dryness on rotovap. The aqueous layer wasextracted 2 times with CH₂Cl₂ (30 ml). The combined extracts were addedto the concentrated 1st organic layer. The organic layer was dried overMgSO₄, filtered and concentrated to give methyl2-(chloromethyl)-4-methoxy-4,5-dihydrooxazole-4-carboxylate (16.25 g, 78mmol, 94% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 4.59 (d, J=10.6 Hz, 1H),4.39 (d, J=10.6 Hz, 1H), 4.15-4.27 (m, 2H), 3.85 (s, 3H), 3.41 (s, 3H).

Step 3: Methyl 2-(chloromethyl)oxazole-4-carboxylate

In a 200 mL round-bottomed flask was added methyl2-(chloromethyl)-4-methoxy-4,5-dihydrooxazole-4-carboxylate (16.25 g, 78mmol) in toluene (38 ml) to give an orange solution. CSA (2.73 g, 11.74mmol) was added. Heated to 70° C. for 1 hour then cooled to 20° C. Theorganic layer was washed with K₂CO₃ 10% wt. in water (23 ml) then withwater (30 ml). Combined the aqueous layers and back extracted withtoluene (45 ml). The combined organic layers were dried over MgSO₄,filtered and concentrated to give 9.8 g as a brown solid. The residuewas purified on ISCO using a RediSep® column (Hexane-Et₂O; 0-90%) togive methyl 2-(chloromethyl)oxazole-4-carboxylate (4.94 g, 28.1 mmol,35.9% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.93 (s, 1H), 4.95 (s,2H), 3.82 (s, 3H).

Step 4: Methyl2-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazole-4-carboxylate

This compound was prepared according to compound 1 step 5. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.91 (s, 1H), 8.10 (s, 1H), 7.70 (s, 1H), 7.07-7.15(m, J=8.6 Hz, 2H), 6.90-6.97 (m, J=8.6 Hz, 2H), 5.25 (s, 2H), 4.38 (t,J=7.0 Hz, 2H), 3.81 (s, 3H), 2.52-2.57 (m, 2H), 1.80 (quin, J=7.3 Hz,2H), 1.47 (quin, J=7.7 Hz, 2H).

Compound 78:2-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-N-(2-nitro-4-(trifluoromethyl)phenyl)oxazole-4-carboxamide

Step 1:2-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazole-4-carboxylicacid

In a 10 mL round-bottomed flask was added methyl2-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazole-4-carboxylate(0.23 g, 0.645 mmol) in THE (2.3 ml) to give a tan suspension. NaOH 0.5Min water (1.291 ml, 0.645 mmol) was added. Stirred at 20° C. for 17hours. More NaOH 0.5M in water (0.581 ml, 0.290 mmol) was added. After19 hours, acidified by slow addition of HCl 0.5M in water (1.936 ml,0.968 mmol) (after addition of 1 mL, the resulting suspension wasstirred for 15 minutes before adding the remaining HCl). The resultingwhite suspension was stirred for 2 hours. Water (1 ml) was added andcontinued stirring for 1 hour. The solids were collected on Buchner andthe cake was washed with water (2×1 mL). Dried the product at 30° C.under high vacuum until constant weight to give2-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazole-4-carboxylicacid (208 mg, 0.608 mmol, 94% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm13.14 (br. s., 1H), 8.77 (s, 1H), 8.09 (s, 1H), 7.68 (s, 1H), 7.04-7.13(m, J=8.2 Hz, 2H), 6.87-6.97 (m, J=8.6 Hz, 2H), 5.21 (s, 2H), 4.37 (t,J=7.0 Hz, 2H), 2.50-2.56 (m, 2H), 1.78 (quin, J=7.3 Hz, 2H), 1.46 (quin,J=7.6 Hz, 2H).

Step 2:2-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-N-(2-nitro-4-(trifluoromethyl)phenyl)oxazole-4-carboxamide

In a 10 mL round-bottomed flask were added2-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazole-4-carboxylicacid (75 mg, 0.219 mmol) in THE (750 μl) and CH₂Cl₂ (750 μl, 11.65 mmol)to give a white suspension. CDI (39.1 mg, 0.241 mmol) was added. Heatedto 40-45° C. After 45 minutes, more CDI (39.1 mg, 0.241 mmol) was added.2-nitro-4-(trifluoromethyl)aniline (49.7 mg, 0.241 mmol) was added andcooled to 20° C. After 19.5 hours, more2-nitro-4-(trifluoromethyl)aniline (49.7 mg, 0.241 mmol) was added.After 26.5 hrs, added DBU (16.51 μl, 0.110 mmol) in 2-MeTHF (2 mL).Heated to 65° C. for 30 minutes then for 18 hours at 20° C. Cooled thesuspension to 0° C. and stirred for 1 hour. The solids were collected onBuchner and the cake was washed with cold 2-MeTHF (3×0.5 mL). Dried theproduct at 40° C. under high vacuum until constant weight to give2-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-N-(2-nitro-4-(trifluoromethyl)phenyl)oxazole-4-carboxamide(61 mg, 0.115 mmol, 52.5% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.44(s, 1H), 9.02 (s, 1H), 8.60 (d, J=8.6 Hz, 1H), 8.44 (s, 1H), 8.16-8.22(m, 1H), 8.10 (s, 1H), 7.70 (s, 1H), 7.09-7.16 (m, J=8.6 Hz, 2H),6.96-7.02 (m, J=8.6 Hz, 2H), 5.32 (s, 2H), 4.39 (t, J=7.0 Hz, 2H), 2.54(t, J=7.4 Hz, 2H), 1.81 (quin, J=7.3 Hz, 2H), 1.48 (quin, J=7.6 Hz, 2H).

Compound 79: (E)-tert-butyl(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)carbamate

Step 1: 4-(4-methoxyphenyl)butan-1-amine

In a 25 mL round-bottomed flask was added1-(4-azidobutyl)-4-methoxybenzene (1.75 g, 8.53 mmol) in THE (4.7 ml) togive a colorless solution. Triphenylphosphine (3.35 g, 12.79 mmol) andwater (0.230 ml, 12.79 mmol) were added. Stirred at 20° C. for 22 hours.Concentrated to dryness on rotovap. The residue was purified on ISCOusing a RediSep® column (DCM-DCM//MeOH/NH₄OH (77.5-22-2.5%); 0-100%) togive 4-(4-methoxyphenyl)butan-1-amine (1.51 g, 8.42 mmol, 99% yield). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.04-7.13 (m, J=8.2 Hz, 2H), 6.78-6.86 (m,2H), 3.71 (s, 3H), 2.43-2.59 (m, 4H), 1.53 (quin, J=7.6 Hz, 2H), 1.32(quin, J=7.2 Hz, 2H).

Step 2: 4-(4-aminobutyl)phenol hydrobromide

In a 50 mL round-bottomed flask was added4-(4-methoxyphenyl)butan-1-amine (1.5 g, 8.37 mmol) in HBr 48% wt. inwater (15 ml, 133 mmol) to give a white suspension. Heated to reflux(120° C.) for 4 hours. Cooled to 0° C. and stirred the resultingsuspension for 1 hour. The solids were collected on Buchner. Dried theproduct at 20° C. under high vacuum until constant weight to give4-(4-aminobutyl)phenol hydrobromide (1.40 g, 5.69 mmol, 68.0% yield). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 9.13 (s, 1H), 7.60 (br. s., 3H), 6.94-7.01(m, J=8.2 Hz, 2H), 6.64-6.69 (m, J=8.6 Hz, 2H), 2.70-2.84 (m, 2H),2.43-2.48 (m, 2H), 1.42-1.62 (m, 4H).

Step 3: tert-butyl (4-(4-hydroxyphenyl)butyl)carbamate

In a 250 mL round-bottomed flask was added 4-(4-aminobutyl)phenolhydrobromide (1.4 g, 5.69 mmol) in dioxane (56 ml) to give a tansuspension. A solution of sodium bicarbonate (1.911 g, 22.75 mmol) inwater (56 ml) was added. Cooled to 0° C. BOC-Anhydride (1.453 ml, 6.26mmol) was added. Slowly warmed to 20° C. After 21 hours, diluted thereaction mixture with EtOAc (209 ml). Separated layers. Washed organiclayer with water (75 mL) then with Brine (75 mL). The organic layer wasdried over MgSO₄, filtered and concentrated to give 1.89 g as acolorless oil. The residue was purified on ISCO using a RediSep® column(Hex-EtOAc; 0-60%) to give tert-butyl(4-(4-hydroxyphenyl)butyl)carbamate (1.23 g, 4.64 mmol, 81% yield). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 9.08 (s, 1H), 6.92-6.99 (m, J=8.2 Hz, 2H),6.77 (t, J=5.7 Hz, 1H), 6.61-6.67 (m, J=8.2 Hz, 2H), 2.90 (q, J=6.7 Hz,2H), 2.43 (t, J=7.4 Hz, 2H), 1.46 (quin, J=7.3 Hz, 2H), 1.29-1.41 (m,11H).

Step 4: (E)-tert-butyl(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)carbamate

In a 25 mL round-bottomed flask were added(E)-4-(chloromethyl)-2-(4-(trifluoromethyl)styryl)oxazole (500 mg, 1.738mmol), tert-butyl (4-(4-hydroxyphenyl)butyl)carbamate (484 mg, 1.825mmol) and K₂CO₃ (264 mg, 1.912 mmol) in DMF (2.8 ml) to give a yellowsuspension. Heated to 75° C. for 48 hours. Cooled to 20° C. MeOH (2.8ml) and water (4.7 ml) were added. Stirred 5 hours. The solids werecollected on Buchner and the cake was washed with water (3×3 mL). Thewet solid was dissolved in warm DMF (2.8 ml). MeOH (2.8 ml) was addedfollowed by slow addition of water (4.7 ml). Stirred the resultingsuspension for 2 days. Added MeOH (2.8 mL). Stirred for 2 hours. Thesolids were collected on Buchner and the cake was washed with MeOH(3×1.5 mL). Dried the product at 30° C. under high vacuum until constantweight to give (E)-tert-butyl(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)carbamate(352 mg, 0.681 mmol, 39.2% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.24(s, 1H), 7.91-8.00 (m, J=8.2 Hz, 2H), 7.73-7.81 (m, J=8.2 Hz, 2H), 7.62(d, J=16.4 Hz, 1H), 7.34 (d, J=16.4 Hz, 1H), 7.06-7.16 (m, J=8.2 Hz,2H), 6.88-6.98 (m, J=8.6 Hz, 2H), 6.73-6.82 (m, 1H), 4.99 (s, 2H), 2.92(q, J=6.7 Hz, 2H), 2.47-2.49 (m, 2H), 1.43-1.56 (m, 2H), 1.28-1.43 (m,11H).

Compound 80:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(pyridin-4-yl)vinyl)oxazole

Step 1: Methyl 2-((diethoxyphosphoryl)methyl)oxazole-4-carboxylate

In a 15 mL round-bottomed flask were added methyl2-(chloromethyl)oxazole-4-carboxylate (compound 85 step 3) (2.0 g, 11.39mmol) in triethyl phosphite (3.59 ml, 20.50 mmol) to give a whitesuspension. Heated to 150° C. for 5.5 hours then cooled to 20° C. andstirred for 16 hours. The residue was purified on ISCO using a RediSep®column (Hexane-Et₂O; 0-100%) to give methyl2-((diethoxyphosphoryl)methyl)oxazole-4-carboxylate (2.95 g, 10.64 mmol,93% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.80-8.85 (m, 1H), 4.05(quin, J=7.3 Hz, 4H), 3.80 (s, 3H), 3.69 (s, 1H), 3.64 (s, 1H), 1.22 (t,J=7.0 Hz, 6H).

Step 2: (E)-methyl 2-(2-(pyridin-4-yl)vinyl)oxazole-4-carboxylate

In a 15 mL round-bottomed flask was added NaH 60% wt. in mineral oil(0.063 g, 1.587 mmol) in THE (1.9 ml) to give a grey suspension. Cooledto −15° C. A solution of methyl2-((diethoxyphosphoryl)methyl)oxazole-4-carboxylate (0.4 g, 1.443 mmol)in THE (2.8 ml) was added dropwise. Stirred at −15° C. for 10 minutes.Isonicotinaldehyde (0.140 ml, 1.486 mmol) was added in one portion.Slowly warmed to 0° C. After 2.5 hours, quenched by adding MeOH (1.0ml). Warmed to 20° C. and stirred for 30 minutes. Concentrated todryness on rotovap. The residue was purified on ISCO using a RediSep®column (CH₂Cl₂—MeOH; 0-100%) to give (E)-methyl2-(2-(pyridin-4-yl)vinyl)oxazole-4-carboxylate (320 mg, 1.390 mmol, 96%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.94 (s, 1H), 8.62 (d, J=5.9 Hz,2H), 7.72 (d, J=6.3 Hz, 2H), 7.61 (d, J=16.4 Hz, 1H), 7.50 (d, J=16.4Hz, 1H), 3.84 (s, 3H).

Step 3: (E)-(2-(2-(pyridin-4-yl)vinyl)oxazol-4-yl)methanol

In a 15 mL round-bottomed flask was added (E)-methyl2-(2-(pyridin-4-yl)vinyl)oxazole-4-carboxylate (0.15 g, 0.652 mmol) inCH₂Cl₂ (4 ml) to give a colorless solution. Cooled to −78° C. DIBAL-H 1Min dichloromethane (1.955 ml, 1.955 mmol) was added slowly to the whitesuspension. Stirred the resulting orange solution for 30 minutes at −78°C. then warmed to 0° C. After 30 minutes, poured reaction mixture in abiphasic mixture of CH₂Cl₂ (7.5 mL) and sat. Rochelle's salt solution(13.5 mL) and stirred vigorously for 1 hour. Separated layers. Extractedaqueous layer with CH₂Cl₂ (2×10 mL). The combined organic layers weredried over MgSO₄, filtered and concentrated to give 108 mg as a whitesolid. The residue was purified on ISCO using a RediSep® column(DCM-DCM(20% MeOH; 0-100%) to give(E)-(2-(2-(pyridin-4-yl)vinyl)oxazol-4-yl)methanol (54 mg, 0.267 mmol,41.0% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (d, J=6.3 Hz, 2H),7.99 (s, 1H), 7.68 (d, J=5.9 Hz, 2H), 7.36-7.51 (m, 2H), 5.23 (t, J=5.6Hz, 1H), 4.41 (d, J=5.6 Hz, 2H).

Step 4: (E)-4-(chloromethyl)-2-(2-(pyridin-4-yl)vinyl)oxazole

In a 10 mL round-bottomed flask was added(E)-(2-(2-(pyridin-4-yl)vinyl)oxazol-4-yl)methanol (54 mg, 0.267 mmol)in CH₂Cl₂ (2.5 ml) to give a white suspension. Cooled to 0° C. SOCl₂(58.5 μl, 0.801 mmol) was added. Stirred at 0° C. for 5 minutes thenwarmed to 20° C. After 30 minutes, quenched the reaction mixture withsat. NaHCO₃ (5 mL). Extracted the mixture with EtOAc (2×5 mL). Thecombined organic layers were washed with water (5 mL) then with brine (5mL). The organic layer was dried over MgSO₄, filtered and concentratedto give (E)-4-(chloromethyl)-2-(2-(pyridin-4-yl)vinyl)oxazole (55 mg,0.249 mmol, 93% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.61 (d, J=5.9Hz, 2H), 8.24 (s, 1H), 7.70 (d, J=5.9 Hz, 2H), 7.40-7.56 (m, 2H), 4.72(s, 2H).

Step 5:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(pyridin-4-yl)vinyl)oxazole

In a 10 mL round-bottomed flask was added NaH 60% wt. in mineral oil(9.71 mg, 0.243 mmol) in DMF (0.75 ml) to give a grey suspension. Cooledto 0° C. 4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenol (52.7 mg, 0.243 mmol)was added. Warmed to 20° C. and stirred for 30 minutes. Cooled to 0° C.(E)-4-(chloromethyl)-2-(2-(pyridin-4-yl)vinyl)oxazole (51 mg, 0.231mmol) was added. Stirred at 0° C. for ca. 1 hour then slowly warmed to20° C. and stirred for 17 hours. Added DMF (0.25 ml) and heated to 40°C. for 4 hours. Cooled to 20° C. and added ca. 5 mg NaH 60% wt inmineral oil. After 23 hours, MeOH (1 ml) was added followed by water (1ml). Stirred the resulting suspension for 17 hours. The solids werecollected on Buchner the cake was washed with water (3×1 mL) then withhexane (1 mL). Dried the product at 40° C. under high vacuum untilconstant weight to give(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(pyridin-4-yl)vinyl)oxazole49.5 mg, 0.123 mmol, 53.3% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.60(d, J=5.9 Hz, 2H), 8.26 (s, 1H), 8.11 (s, 1H), 7.66-7.73 (m, 3H),7.40-7.56 (m, 2H), 7.05-7.14 (m, J=8.6 Hz, 2H), 6.90-6.98 (m, J=8.6 Hz,2H), 4.99 (s, 2H), 4.39 (t, J=7.0 Hz, 2H), 2.52-2.58 (m, 2H), 1.81(quin, J=7.3 Hz, 2H), 1.48 (quin, J=7.6 Hz, 2H).

Compounds 81-85

Compounds 81-85 were prepared according to the procedure for compound 80steps 1 to 5 from the appropriate starting pyridine.

Compound 81:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(3-fluoropyridin-4-yl)vinyl)oxazole

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.65 (d, J=2.0 Hz, 1H), 8.48 (d, J=5.1Hz, 1H), 8.29 (s, 1H), 8.11 (s, 1H), 7.88-7.96 (m, 1H), 7.70 (s, 1H),7.42-7.58 (m, 2H), 7.04-7.14 (m, J=8.6 Hz, 2H), 6.91-6.99 (m, J=8.6 Hz,2H), 5.00 (s, 2H), 4.39 (t, J=7.0 Hz, 2H), 2.52-2.58 (m, 2H), 1.81(quin, J=7.3 Hz, 2H), 1.48 (quin, J=7.6 Hz, 2H).

Compound 82:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(pyridin-3-yl)vinyl)oxazole

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.84-8.91 (m, 1H), 8.54 (dd, J=4.7, 0.8Hz, 1H), 8.22 (s, 1H), 8.19 (d, J=7.8 Hz, 1H), 8.11 (s, 1H), 7.70 (s,1H), 7.56 (d, J=16.4 Hz, 1H), 7.44 (dd, J=8.0, 4.9 Hz, 1H), 7.32 (d,J=16.8 Hz, 1H), 7.06-7.13 (m, J=8.6 Hz, 2H), 6.90-6.98 (m, J=8.2 Hz,2H), 4.98 (s, 2H), 4.39 (t, J=7.0 Hz, 2H), 2.52-2.58 (m, 2H), 1.81(quin, J=7.2 Hz, 2H), 1.48 (quin, J=7.6 Hz, 2H).

Compound 83:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(2-fluoropyridin-3-yl)vinyl)oxazole

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.42-8.50 (m, 1H), 8.20-8.28 (m, 2H),8.11 (s, 1H), 7.70 (s, 1H), 7.50 (d, J=16.4 Hz, 1H), 7.41-7.47 (m, 1H),7.33 (d, J=16.4 Hz, 1H), 7.06-7.12 (m, J=8.2 Hz, 2H), 6.91-6.97 (m,J=8.6 Hz, 2H), 4.99 (s, 2H), 4.39 (t, J=7.0 Hz, 2H), 2.52-2.56 (m, 2H),1.81 (quin, J=7.3 Hz, 2H), 1.48 (quin, J=7.6 Hz, 2H).

Compound 84:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(pyridin-2-yl)vinyl)oxazole

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.63 (d, J=4.3 Hz, 1H), 8.24 (s, 1H),8.11 (s, 1H), 7.85 (td, J=7.6, 1.6 Hz, 1H), 7.67-7.74 (m, 2H), 7.57 (d,J=16.0 Hz, 1H), 7.44 (d, J=16.0 Hz, 1H), 7.36 (dd, J=7.2, 4.9 Hz, 1H),7.05-7.14 (m, J=8.6 Hz, 2H), 6.91-6.98 (m, J=8.6 Hz, 2H), 4.98 (s, 2H),4.39 (t, J=7.0 Hz, 2H), 2.52-2.58 (m, 2H), 1.81 (quin, J=7.3 Hz, 2H),1.48 (quin, J=7.6 Hz, 2H).

Compound 85:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-(3-fluoropyridin-2-yl)vinyl)oxazole

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.52 (d, J=4.7 Hz, 1H), 8.27 (s, 1H),8.11 (s, 1H), 7.78-7.85 (m, 1H), 7.60-7.72 (m, 2H), 7.43-7.54 (m, 2H),7.06-7.14 (m, J=8.6 Hz, 2H), 6.90-6.98 (m, J=8.6 Hz, 2H), 4.99 (s, 2H),4.39 (t, J=7.0 Hz, 2H), 2.52-2.57 (m, 2H), 1.81 (quin, J=7.3 Hz, 2H),1.48 (quin, J=7.6 Hz, 2H).

Compound 86:(E)-3-hydroxy-N-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)propanamide

Step 1: tert-butyl 3-(trityloxy)propanoate

In a 50 mL round-bottomed flask were added tert-butyl3-hydroxypropanoate (0.55 g, 3.76 mmol) and pyridine (0.913 ml, 11.29mmol) in CH₂Cl₂ (14 ml) to give a colorless solution. Cooled to 0° C.Trityl chloride (1.049 g, 3.76 mmol) was added in portions. Slowlywarmed to 20° C. After 22 hours, concentrated to dryness on rotovap. Theresulting white solid was suspended in EtOAc (30 mL). Washed with water(15 mL), 5% citric acid (20 mL) and brine (10 mL). The organic layer wasdried over MgSO₄, filtered and concentrated to give 1.45 g as a whiteoily solid. The residue was purified on ISCO using a RediSep® column(Hex-EtOAc; 0-20%) to give tert-butyl 3-(trityloxy)propanoate (915 mg,2.355 mmol, 62.6% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.30-7.41 (m,12H), 7.22-7.30 (m, 3H), 3.17 (t, J=6.1 Hz, 2H), 2.45 (t, J=6.1 Hz, 2H),1.40 (s, 9H).

Step 2: 3-(trityloxy)propanoic acid

In a 25 mL round-bottomed flask were added tert-butyl3-(trityloxy)propanoate (0.915 g, 2.355 mmol) in EtOH (9 ml) to give acolorless solution. NaOH 6M in water (0.785 ml, 4.71 mmol) was added.Heated to reflux. After 4.5 hours, concentrated to dryness on rotovap.The residue was dissolved in CH₂Cl₂ (40 mL) and washed with 3% citricacid solution (30 mL). Washed organic layer with brine (20 mL). Theorganic layer was dried over MgSO₄, filtered and concentrated todryness. The resulting white solid was suspended in i-Pr₂O (20 mL) andstirred at 20° C. for 18 hours. The solids were collected on Buchner andthe cake was washed with i-Pr₂O (3×3 mL). Dried the product at 30° C.under high vacuum until constant weight to give 3-(trityloxy)propanoicacid (575 mg, 1.730 mmol, 73.4% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.22 (br. s., 1H), 7.30-7.41 (m, 12H), 7.22-7.30 (m, 3H), 3.19 (t,J=6.5 Hz, 2H), 2.47 (s, 2H).

Step 3:(E)-4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butan-1-aminehydrochloride

In a 15 mL round-bottomed flask was added (E)-tert-butyl(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)carbamate(0.3 g, 0.581 mmol) in MeOH (1.5 ml) to give a white suspension. HCl 4Min dioxane (0.726 ml, 2.90 mmol) was added. Stirred the resulting thintan suspension for 3 hours. EtOAc (4.5 ml) was added and stirred thesuspension for 1 hour. The solids were collected on Buchner and the cakewas washed with EtOAc (3×1 mL). Dried the product at 20° C. under highvacuum until constant weight to give(E)-4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butan-1-aminehydrochloride (232 mg, 0.512 mmol, 88% yield). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 8.25 (s, 1H), 7.95 (d, J=8.2 Hz, 2H), 7.72-7.89 (m, 5H), 7.61 (d,J=16.4 Hz, 1H), 7.34 (d, J=16.4 Hz, 1H), 7.10-7.17 (m, J=8.6 Hz, 2H),6.92-7.00 (m, J=8.6 Hz, 2H), 4.99 (s, 2H), 2.77 (br. s., 2H), 2.52-2.57(m, 2H), 1.45-1.65 (m, 4H).

Step 4:(E)-N-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-3-(trityloxy)propanamide

In a 15 mL round-bottomed flask were added(E)-4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butan-1-aminehydrochloride (0.150 g, 0.331 mmol) and 3-(trityloxy)propanoic acid(0.121 g, 0.364 mmol) in DMF (2.25 ml). DIPEA (0.145 ml, 0.828 mmol) andEDC (0.079 g, 0.414 mmol) were added. Stirred at 20° C. for 20 hours.3-(trityloxy)propanoic acid (compound 94 step 2) (0.220 g, 0.662 mmol),DIPEA (0.260 ml, 1.490 mmol) and EDC (0.140 g, 0.729 mmol) were added.After 43 hours, the reaction mixture was poured into EtOAc (25 mL) andwashed with water (10 mL) then HCl 0.5M (10 mL) then 10% KHCO₃ (10 mL)then brine (10 mL). The organic layer was dried over MgSO₄, filtered andconcentrated to give a colorless oil. The residue was purified on ISCOusing a RediSep® column (Hex-EtOAc; 0-100%) to give(E)-N-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-3-rityloxy)propanamide(223 mg, 0.305 mmol, 92% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.23(s, 1H), 7.95 (d, J=7.8 Hz, 3H), 7.76 (d, J=8.2 Hz, 2H), 7.61 (d, J=16.4Hz, 1H), 7.33-7.39 (m, 7H), 7.30 (t, J=7.6 Hz, 6H), 7.20-7.27 (m, 3H),7.02-7.10 (m, J=8.6 Hz, 2H), 6.87-6.94 (m, J=8.6 Hz, 2H), 4.98 (s, 2H),3.04-3.17 (m, 4H), 2.45-2.48 (m, 2H), 2.34 (t, J=6.3 Hz, 2H), 1.49-1.61(m, 2H), 1.36-1.49 (m, 2H).

Step 5:(E)-3-hydroxy-N-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)propanamide

In a 25 μmL round-bottomed flask were added(E)-N-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-3-(trityloxy)propanamide(0.22 g, 0.301 mmol) in MeOH (3 ml) and CHCl₃ (3 ml). p-TsOH (5.73 mg,0.030 mmol) was added. Stirred at 20° C. for 3.5 hours. Concentrated thereaction mixture to dryness on rotovap. The residue was purified on ISCOusing a RediSep® column (CH₂Cl₂—MeOH) to give(E)-3-hydroxy-N-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)propanamide (142 mg, 0.291 mmol,97% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.24 (s, 1H), 7.95 (d, J=8.2Hz, 2H), 7.71-7.80 (m, 3H), 7.62 (d, J=16.4 Hz, 1H), 7.34 (d, J=16.8 Hz,1H), 7.07-7.15 (m, J=8.6 Hz, 2H), 6.90-6.98 (m, J=8.6 Hz, 2H), 4.99 (s,2H), 4.52 (t, J=5.3 Hz, 1H), 3.54-3.61 (m, 2H), 3.04 (q, J=6.7 Hz, 2H),2.52-2.56 (m, 2H), 2.20 (t, J=6.7 Hz, 2H), 1.52 (quin, J=7.4 Hz, 2H),1.38 (quin, J=7.4 Hz, 2H).

Compound 87:(E)-3-oxo-3-((4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)amino)propyl dimethylcarbamate

In a 5 mL round-bottomed flask was added NaH 60% wt. in mineral oil(3.60 mg, 0.090 mmol) in DMF (0.5 ml) to give a grey suspension.(E)-3-hydroxy-N-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)propanamide(compound 94) (40 mg, 0.082 mmol) was added. Stirred at 20° C. for 30minutes. Cooled to 0° C. Dimethylcarbamoyl chloride (8.28 μl, 0.090mmol) was added dropwise. After 30 minutes, dimethylcarbamoyl chloride(8.28 μl, 0.090 mmol) was added. After 1 hour, added NaH 60% wt. inmineral oil (1.638 mg, 0.041 mmol) followed by dimethylcarbamoylchloride (8.28 μl, 0.090 mmol). After 1.5 hour, MeOH (0.5 ml) was addedfollowed by dropwise addition of water (0.5 ml). The white suspensionwas stirred for 1 hour. The solids were collected on Buchner and thecake was washed with MeOH:Water (1:1, 3×0.75 mL) followed by Hexane(2×0.5 mL). Dried the product at 30° C. under high vacuum until constantweight to give(E)-3-oxo-3-((4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)amino)propyldimethylcarbamate (40 mg, 0.071 mmol, 87% yield) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.24 (s, 1H), 7.92-8.00 (m, J=8.2 Hz, 2H),7.89 (t, J=5.5 Hz, 1H), 7.73-7.80 (m, J=8.2 Hz, 2H), 7.61 (d, J=16.4 Hz,1H), 7.34 (d, J=16.8 Hz, 1H), 7.06-7.15 (m, J=8.2 Hz, 2H), 6.90-6.98 (m,J=8.6 Hz, 2H), 4.99 (s, 2H), 4.13 (t, J=6.3 Hz, 2H), 3.06 (q, J=6.5 Hz,2H), 2.70-2.83 (m, 6H), 2.52 (br. s., 2H), 2.35 (t, J=6.3 Hz, 2H), 1.52(quin, J=7.5 Hz, 2H), 1.38 (quin, J=7.1 Hz, 2H).

Compound 88:(E)-4-((4-(4-(1H-1,2,4-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

Step 1: 1-(4-(4-methoxyphenyl)butyl)-1H-1,2,4-triazole

1H-1,2,4-triazole (802 mg, 11.61 mmol) was dissolved in THE (15 ml) andcooled to 0° C., NaH 60% (418 mg, 10.45 mmol) was added and stirred for1 h at rt. This mixture was added to a solution of4-(4-methoxyphenyl)butyl methanesulfonate (600 mg, 2.323 mmol) in DMF(4.00 ml) and THE (3.0 ml) in a microwave tube which was sealed andheated to 60° C. for 3 h. The mixture was diluted with EA (20 ml),filtered through a pad of celite. The filtrate was concentrated todryness and the residue was purified using ISCO column (DCM to 40% AcOEtin DCM) to give title compound (0.45 g, 84% yield) as a colorless oil.¹H NMR (400 MHz, CDCl₃) δ ppm 1.59 (t, J=7.63 Hz, 2H) 1.83-2.00 (m, 2H)2.58 (t, J=7.63 Hz, 2H) 3.78 (s, 3H) 4.16 (t, J=7.24 Hz, 2H) 6.82 (m,J=8.61 Hz, 2H) 7.05 (m, J=8.61 Hz, 2H) 7.93 (s, 1H) 8.00 (s, 1H).

Step 2: 4-(4-(1H-1,2,4-triazol-1-yl)butyl)phenol

In a 25 ml flask was added1-(4-(4-methoxyphenyl)butyl)-1H-1,2,4-triazole (0.52 g, 2.248 mmol) inhydrogen bromide 48% in water (1.526 ml, 13.49 mmol) to give a lightyellow solution. The reaction mixture was heated to 90° C. and stirredfor 18 h, then cooled to rt. EtOAc (30 ml) and THE (20 ml) was added.The organic layer was washed with saturated NaHCO₃ solution (10 ml) andwater (10 ml), dried and concentrated to give title compound 0.48 g. ¹HNMR (400 MHz, CDCl₃) δ ppm 1.53 (t, J=7.63 Hz, 2H), 1.77-1.93 (m, 2H),2.52 (t, J=7.43 Hz, 2H), 4.11 (t, J=7.04 Hz, 2H), 6.70 (d, J=8.22 Hz,2H), 6.93 (d, J=8.61 Hz, 2H) 7.88 (s, 1H), 7.97 (s, 1H).

Step 3:(E)-4-((4-(4-(1H-1,2,4-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

In an 8 ml vial were added(E)-4-(chloromethyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole (40mg, 0.131 mmol) and K₂CO₃ (19.90 mg, 0.144 mmol) in DMF (253 μl, 3.27mmol) to give a yellow suspension. The mixture was heated to 75° C. for6 h, then cooled to 20° C. MeOH (220 μl) and H₂O (360 μl) were added,stirred for 10 min. The solid were collected, washed with water (3×0.5mL), dried under high vacuum. The crude was purified using an ISCOcolumn (A: Pure DCM, B: 20% MeOH in DCM. 0% B to 30% B) to give titlecompound (40 mg, 62.8% yield) as beige solid, ¹H NMR (400 MHz, DMSO-d6)δ ppm 1.44 (t, J=7.43 Hz, 2H) 1.66-1.83 (m, 2H) 2.50-2.54 (m, 2H) 4.16(t, J=6.85 Hz, 2H) 4.97 (s, 2H) 6.92 (d, J=8.61 Hz, 2H) 7.08 (d, J=8.22Hz, 2H) 7.37 (d, J=16.43 Hz, 1H) 7.52-7.67 (m, 2H), 7.76 (d, J=10.56 Hz,1H) 7.92 (s, 1H) 8.07-8.19 (m, 1H) 8.24 (s, 1H) 8.48 (s, 1H) and

Compound 89:(E)-2-(2-(4-(4-(1H-1,2,4-triazol-1-yl)butyl)phenoxy)-4-(trifluoromethyl)styryl)-4-((4-(4-(1H-1,2,4-triazol-1-yl)butyl)phenoxy)methyl)oxazole

(5 mg, 5.6% yield)¹H NMR (400 MHz, CD₃OD) δ ppm 1.49-1.67 (m, 4H) 1.88(dt, J=15.75, 7.97 Hz, 4H) 2.57 (t, J=7.43 Hz, 2H) 2.66 (t, J=7.63 Hz,2H) 4.23 (dt, J=11.05, 6.99 Hz, 4H) 4.96 (s, 2H) 6.90 (d, J=8.22 Hz, 2H)6.97 (m, J=8.22 Hz, 2H) 7.03 (s, 1H) 7.07 (m, J=8.22 Hz, 2H) 7.20-7.27(m, 3H) 7.42 (d, J=7.83 Hz, 1H) 7.86 (d, J=16.83 Hz, 1H) 7.92 (s, 1H)7.96 (d, J=2.74 Hz, 3H) 8.43 (d, J=9.00 Hz, 2H)

Compound 90:(E)-4-((4-(4-(1H-tetrazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

Step 1: 1-(4-(4-methoxyphenyl)butyl)-1H-tetrazole

1H-tetrazole (987 mg, 14.09 mmol) was dissolved in THE (15 ml) andcooled to 0° C., NaH (499 mg, 12.46 mmol) was added and stirred for 1 hat rt. This mixture was added to a solution of 4-(4-methoxyphenyl)butylmethanesulfonate (700 mg, 2.71 mmol) in DMF (3.00 ml) and THE (3.00 ml)in a microwave tube that was sealed and heated to 60° C. for 3 h. Themixture was diluted with EA (20 ml) and filtered through a pad ofcelite. The filtrate was concentrated to dryness, and the residue waspurified using an ISCO column (DCM to 40% AcOEt in DCM) to give 0.17 gof the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.63 (t, J=7.63 Hz,2H) 1.88-2.06 (m, 2H) 2.61 (t, J=7.43 Hz, 2H) 3.78 (s, 2H) 4.41 (t,J=7.24 Hz, 2H) 6.76-6.89 (m, 2H) 7.05 (m, J=8.61 Hz, 2H) 8.51 (s, 1H)and the regioisomer, 2-(4-(4-methoxyphenyl)butyl)-2H-tetrazole.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.62 (t, J=7.63 Hz, 2H) 1.95-2.15 (m, 2H)2.60 (t, J=7.63 Hz, 2H) 3.78 (s, 2H) 4.65 (t, J=7.04 Hz, 2H) 6.73-6.89(m, 2H) 7.06 (m, J=8.61 Hz, 2H) 8.49 (s, 1H)

Step 2: 4-(4-(1H-tetrazol-1-yl)butyl)phenol

This compound was prepared in a similar fashion as compound 1 step 4with the previous intermediate. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.50-1.66(m, 2H) 1.85-1.97 (m, 2H) 2.54 (t, J=7.43 Hz, 2H) 4.36 (t, J=7.04 Hz,2H) 6.71 (m, J=8.61 Hz, 2H) 6.92 (m, J=8.22 Hz, 2H) 8.54 (s, 1H)

Step 3:(E)-4-((4-(4-(1H-tetrazol-1-yl)butyl)phenoxy)methy)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

This compound was prepared in a similar fashion as compound 1 step 5with the previous intermediate. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.47 (t,J=7.63 Hz, 2H) 1.73-1.92 (m, 2H) 2.50-2.55 (m, 2H) 4.45 (t, J=7.04 Hz,2H) 4.97 (s, 2H) 6.93 (m, J=8.61 Hz, 2H) 7.08 (m, J=8.61 Hz, 2H) 7.37(d, J=16.43 Hz, 1H) 7.57 (d, J=16.43 Hz, 1H) 7.63 (d, J=8.22 Hz, 1H)7.77 (d, J=10.96 Hz, 1H) 8.14 (t, J=8.02 Hz, 1H) 8.24 (s, 1H) 9.38 (s,1H)

Compound 91:(E)-4-((4-(4-(1H-pyrazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

Step 1: 1-(4-(4-methoxyphenyl)butyl)-1H-pyrazole

This compound was prepared in a similar fashion as compound 88 step 1with 1H-pyrazole. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.60 (br. s., 2H)1.81-1.97 (m, 2H) 2.57 (t, J=7.63 Hz, 2H) 3.78 (s, 3H) 4.13 (t, J=7.04Hz, 2H) 6.22 (t, J=1.96 Hz, 1H) 6.81 (m, J=8.61 Hz, 2H) 7.06 (m, J=8.61Hz, 2H) 7.34 (d, J=2.35 Hz, 1H) 7.49 (d, J=1.57 Hz, 1H)

Step 2: 4-(4-(1H-pyrazol-1-yl)butyl)phenol

This compound was prepared in a similar fashion as compound 88 step 2with the previous intermediate. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.41-1.61(m, 2H) 1.73-1.92 (m, 2H) 2.51 (t, J=7.63 Hz, 2H) 4.14 (t, J=7.04 Hz,2H) 6.25 (t, J=1.96 Hz, 1H) 6.61-6.70 (m, 2H) 6.95 (m, J=8.61 Hz, 2H)7.45 (d, J=1.96 Hz, 1H) 7.57 (d, J=2.35 Hz, 1H)

Step 3:(E)-4-((4-(4-(1H-pyrazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

This compound was prepared in a similar fashion as compound 88 step 3with the previous intermediate. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.59-1.65(m, 2H) 1.81-1.98 (m, 2H) 2.58 (t, J=7.43 Hz, 2H) 4.13 (t, J=7.04 Hz,2H) 5.02 (s, 2H) 6.16-6.32 (m, 1H) 6.90 (m, J=8.61 Hz, 2H) 7.07 (m,J=8.61 Hz, 2H) 7.13 (d, J=16.43 Hz, 1H) 7.34 (d, J=1.96 Hz, 1H) 7.38 (d,J=10.56 Hz, 1H) 7.44 (d, J=8.22 Hz, 1H) 7.47-7.53 (m, 1H) 7.60-7.68 (m,2H) 7.69 (s, 1H)

Compound 92:(E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(4-methyl-1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazole

Step 1: 1-(4-(4-methoxyphenyl)butyl)-4-methyl-1H-1,2,3-triazole

Into a macrowave tube, 4-methyl-1H-1,2,3-triazole (473 mg, 5.69 mmol)was dissolved in THE (10 ml) and cooled to 0° C., NaH (341 mg, 8.54mmol) was added and stirred for 1 h at rt. A solution of4-(4-methoxyphenyl)butyl methanesulfonate (490 mg, 1.897 mmol) in DMF(2.00 ml) and THE (1.0 ml) was then added and heated to 60° C. for 3 h.The mixture was diluted with EA (20 ml) and filtered through a pad ofcelite. The filtrate was concentrated to dryness. The crude was purifiedusing ISCO column (DCM to 40% EA in DCM) to give two isomers. The titlecompound (0.13 g), ¹H NMR (400 MHz, CDCl₃) δ ppm 1.57-1.64 (m, 2H)1.88-2.02 (m, 2H) 2.29 (s, 2H) 2.57 (t, J=7.63 Hz, 2H) 3.78 (s, 3H) 4.35(t, J=7.04 Hz, 2H) 6.76-6.86 (m, 2H) 7.06 (m, J=8.22 Hz, 2H) 7.31 (s,1H) and

2-(4-(4-methoxyphenyl)butyl)-4-methyl-2H-1,2,3-triazole (0.18 g). ¹H NMR(400 MHz, CDCl₃) δ ppm 1.60-1.68 (m, 2H) 1.80-1.97 (m, 2H) 2.26 (s, 1H)2.33 (s, 2H) 2.52-2.66 (m, 2H) 3.78 (s, 3H) 4.16-4.36 (m, 2H) 6.82 (m,J=8.22 Hz, 2H) 7.05 (d, J=8.61 Hz, 2H) 7.32 (m, 1H)

Step 2: 4-(4-(4-methyl-1H-1,2,3-triazol-1-yl)butyl)phenol

This compound was prepared in a similar fashion as compound 88 step 2with 1-(4-(4-methoxyphenyl)butyl)-4-methyl-1H-1,2,3-triazole. ¹H NMR(400 MHz, CD₃OD) δ ppm 1.44-1.58 (m, 2H) 1.78-1.97 (m, 2H) 2.26 (s, 3H)2.51 (t, J=7.63 Hz, 2H) 4.34 (t, J=7.04 Hz, 2H) 6.62-6.71 (m, 2H) 6.94(d, J=8.22 Hz, 2H) 7.40 (s, 1H)

Step 3:(E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(4-methyl-1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazole

This compound was prepared in a similar fashion as compound 88 step 3with the previous intermediate. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.63-1.68(m, 2H) 1.81-1.97 (m, 2H) 2.26 (s, 1H) 2.33 (s, 2H) 2.59 (td, J=7.43,2.74 Hz, 2H) 4.18-4.38 (m, 2H) 5.02 (s, 2H) 6.91 (d, J=8.61 Hz, 2H) 7.06(s, 1H) 7.09 (d, J=9.00 Hz, 1H) 7.15 (s, 1H) 7.21 (s, 1H) 7.37 (d,J=10.56 Hz, 1H) 7.41-7.47 (m, 1H) 7.60-7.68 (m, 2H) 7.69 (s, 1H)

Compound 93:(E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(3-methyl-1H-1,2,4-triazol-1-yl)butyl)phenoxy)methyl)oxazole

Step 1: 1-(4-(4-methoxyphenyl)butyl)-3-methyl-1H-1,2,4-triazole

This compound was prepared in a similar fashion as compound 88 step 1with 3-methyl-1H-1,2,4-triazole. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.76-1.96(m, 2H) 2.40 (d, J=10.56 Hz, 2H) 2.58 (t, J=7.63 Hz, 2H) 3.78 (s, 3H)4.05 (q, J=7.17 Hz, 2H) 6.82 (m, J=8.61 Hz, 2H) 7.06 (m, J=8.22 Hz, 2H)

Step 2: 4-(4-(3-methyl-1H-1,2,4-triazol-1-yl)butyl)phenol

This compound was prepared in a similar fashion as compound 88 step 2with the previous intermediate. ¹H NMR (400 MHz, METHANOL-d4) δ ppm1.45-1.64 (m, 2H) 1.82 (dd, J=15.06, 7.24 Hz, 2H) 2.32 (s, 2H) 2.41 (s,1H) 2.53 (td, J=7.53, 3.33 Hz, 2H) 4.12 (td, J=6.95, 4.11 Hz, 2H) 6.67(d, J=8.22 Hz, 2H) 6.90-7.01 (m, 2H) 7.77-7.79 (m, 1H)

Step 3:(E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(3-methyl-1H-1,2,4-triazol-1-yl)butyl)phenoxy)methyl)oxazole

This compound was prepared in a similar fashion as compound 88 step 3with the previous intermediate. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.59-1.67(m, 2H) 1.79-1.96 (m, 2H) 2.40 (d, J=11.35 Hz, 3H) 2.59 (t, J=7.63 Hz,2H) 4.06 (q, J=7.43 Hz, 2H) 5.02 (s, 2H) 6.91 (m, J=8.61 Hz, 2H) 7.07(m, J=8.61 Hz, 2H) 7.13 (d, J=16.43 Hz, 1H) 7.38 (d, J=10.56 Hz, 1H)7.44 (d, J=8.22 Hz, 1H) 7.60-7.68 (m, 2H) 7.69 (s, 1H)

Compound 94:(E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(5-methyl-2H-tetrazol-2-yl)butyl)phenoxy)methyl)oxazole

Step 1: 1-(4-(4-methoxyphenyl)butyl)-5-methyl-1H-tetrazole and2-(4-(4-methoxyphenyl)butyl)-5-methyl-2H-tetrazole

Into a microwave tube, 5-methyl-1H-tetrazole (797 mg, 9.48 mmol) wasdissolved in THE (10 ml) and cooled to 0° C., NaH 60% (341 mg, 8.54mmol) was added and stirred for 1 h at rt. A solution of4-(4-methoxyphenyl)butyl methanesulfonate (490 mg, 1.897 mmol) in DMF(2.00 ml) and THE (1.0 ml) was then added and heated to 6° C. for 3 h.The mixture was diluted with EA (20 ml) and filtered through a pad ofcelite. The filtrate was concentrated to dryness, and the residue waspurified using ISCO column (DCM to 40% EA in DCM) to give a mixture of2-(4-(4-methoxyphenyl)butyl)-5-methyl-2H-tetrazole and1-(4-(4-methoxyphenyl)butyl)-5-methyl-1H-tetrazole (0.34 g),LRMS+H⁺=247.2

Step 2: 4-(4-(5-methyl-1H-tetrazol-1-yl)butyl)phenol and4-(4-(5-methyl-2H-tetrazol-2-yl)butyl)phenol

In a 25 ml flask was added a mix of1-(4-(4-methoxyphenyl)butyl)-5-methyl-1H-tetrazole and2-(4-(4-methoxyphenyl)butyl)-5-methyl-2H-tetrazole (0.340 g, 1.380 mmol)in hydrogen bromide 48% in water (0.937 ml, 8.28 mmol) to give a lightyellow solution. The reaction mixture was heated to 90° C. and stirredfor 18 h, then cooled to rt. EA (20 ml) and THE (10 ml) were added. Theorganic layer was washed with sat. NaHCO₃ (5 ml) and water (10 ml). Itwas dried and concentrated to dryness to give a mixture of4-(4-(5-methyl-2H-tetrazol-2-yl)butyl)phenol and4-(4-(5-methyl-1H-tetrazol-1-yl)butyl)phenol (0.32 g). LRMS+H⁺:233.1

Step 3:(E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(5-methyl-2H-tetrazol-2-yl)butyl)phenoxy)methyl)oxazole

In a 8 ml vial were added the mix of(E)-4-(chloromethyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole and(E)-4-(chloromethyl)-2-(2-fluoro-4-(trifluoromethyl)styryl) oxazole (40mg, 0.131 mmol), K₂CO₃ (19.90 mg, 0.144 mmol) in DMF (300 μl) to give ayellow suspension. The reaction mixture was heated to 75° C. for 6 h andthen cooled to 20° C. Methanol (220 μl) and water (360 μl) were added.The solid was collected, washed with water (3×0.5 mL). The crude wasfurther purified by preparative HPLC (MeOH-water 5% HCO₂H; 35%-100%) togive 20 mg of the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm1.59-1.68 (m, 2H) 2.01 (quin, J=7.43 Hz, 2H) 2.47-2.54 (m, 3H) 2.55-2.66(m, 2H) 4.55 (t, J=7.04 Hz, 2H) 5.02 (s, 2H) 6.85-6.97 (m, 2H) 7.05-7.10(m, 2H) 7.13 (d, J=16.43 Hz, 1H) 7.38 (d, J=10.56 Hz, 1H) 7.44 (d,J=8.22 Hz, 1H) 7.61-7.68 (m, 2H) 7.69 (s, 1H).

Compound 95:(E)-2-(1-(4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethanol

This compound was prepared in a similar fashion as compound 8 withbut-3-yn-1-ol and(E)-4-((4-(4-azidobutyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole.¹H NMR (400 MHz, DMSO-d6) δ ppm 1.49 (quin, J=7.60 Hz, 2H) 1.78 (quin,J=7.24 Hz, 2H) 2.51-2.57 (m, 2H) 2.74 (t, J=7.04 Hz, 2H) 3.56-3.65 (m,2H) 4.31 (t, J=7.04 Hz, 2H) 4.66 (t, J=5.28 Hz, 1H) 4.99 (s, 2H) 6.94(m, J=8.61 Hz, 2H) 7.10 (m, J=8.61 Hz, 2H) 7.39 (d, J=16.43 Hz, 1H) 7.59(d, J=16.82 Hz, 1H) 7.64 (d, J=8.61 Hz, 1H) 7.78 (d, J=10.96 Hz, 1H)7.83 (s, 1H) 8.16 (t, J=7.63 Hz, 1H) 8.26 (s, 1H). LRMS+H⁺: 531.0.

Compound 96:(E)-2-(1-(4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethyl(2-methoxyethyl)carbamate

This compound was prepared in a similar fashion as compound 69 withcompound 95 and 1-isocyanato-2-methoxyethane. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.49 (quin, J=7.20 Hz, 2H) 1.78 (quin, J=7.24 Hz, 2H) 2.52-2.58(m, 2H) 2.89 (t, J=6.85 Hz, 2H) 3.07-3.14 (m, 2H) 3.21 (s, 3H) 4.15 (t,J=6.85 Hz, 2H) 4.32 (t, J=7.04 Hz, 2H) 4.99 (s, 2H) 6.94 (m, J=8.61 Hz,2H) 7.10 (m, J=8.61 Hz, 2H) 7.15 (t, J=5.48 Hz, 1H) 7.39 (d, J=16.43 Hz,1H) 7.59 (d, J=16.43 Hz, 1H) 7.65 (d, J=8.22 Hz, 1H) 7.79 (d, J=10.96Hz, 1H) 7.90 (s, 1H) 8.16 (t, J=7.63 Hz, 1H) 8.26 (s, 1H).

Compound 97:(E)-2-(1-(4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethylcyclopentylcarbamate

This compound was prepared in a similar fashion as compound 69 withcompound 95 and isocyanatocyclopentane. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.30-1.63 (m, 8H) 1.68-1.84 (m, 4H) 2.51-2.57 (m, 2H) 2.89 (t, J=6.85Hz, 2H) 4.15 (t, J=6.65 Hz, 2H) 4.32 (t, J=7.04 Hz, 2H) 4.99 (s, 2H)6.94 (d, J=8.61 Hz, 2H) 7.02-7.15 (m, 3H) 7.39 (d, J=16.43 Hz, 1H) 7.59(d, J=16.43 Hz, 1H) 7.64 (d, J=7.83 Hz, 1H) 7.78 (d, J=10.96 Hz, 1H)7.89 (s, 1H) 8.16 (t, J=7.83 Hz, 1H) 8.26 (s, 1H).

Compound 98:(E)-2-(1-(4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazol-4-yl)ethylisopropylcarbamate

This compound was prepared in a similar fashion as compound 69 withcompound 95 and 2-isocyanatopropane. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.02 (d, J=6.26 Hz, 6H) 1.49 (quin, J=7.40 Hz, 2H) 1.78 (quin, J=7.40Hz, 1H) 2.51-2.57 (m, 2H) 2.89 (t, J=6.85 Hz, 2H) 3.51-3.64 (m, 1H) 4.15(t, J=6.65 Hz, 2H) 4.32 (t, J=7.04 Hz, 2H) 4.99 (s, 2H) 6.94 (m, J=8.61Hz, 2H) 7.01 (d, J=7.04 Hz, 1H) 7.10 (m, J=8.61 Hz, 2H) 7.39 (d, J=16.43Hz, 1H) 7.59 (d, J=16.43 Hz, 1H) 7.64 (d, J=8.22 Hz, 1H) 7.78 (d,J=10.56 Hz, 1H) 7.89 (s, 1H) 8.16 (t, J=7.63 Hz, 1H) 8.26 (s, 1H).

Compound 99:(E)-4-((4-(4-(1H-imidazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-nitrostyryl)oxazole

Step 1: 1-(4-(4-(benzyloxy)phenyl)butyl)-1H-imidazole

NaH 60% (0.074 g, 1.843 mmol) was added to a solution of imidazole(0.125 g, 1.843 mmol) in DMF (2.5 ml) at 0° C. and stirred 30 min at 0°C. Then, 1-(benzyloxy)-4-(4-iodobutyl)benzene (See the method describedin WO 01/77107A1) (0.54 g, 1.474 mmol) in DMF (2.5 ml) was added slowly.It was brought to rt for 3 h and quenched with a NH₄Cl solution andextracted 3× with EA. The organic phases were combined and washed withwater, Na₂SO₄ dried, filtered and the solvent removed to give 0.45 g ofthe title compound crude. LRMS+H⁺307.0.

Step 2: 4-(4-(1H-imidazol-1-yl)butyl)phenol

A mixture of 1-(4-(4-(benzyloxy)phenyl)butyl)-1H-imidazole (0.45 g, 1.47mmol) and Pd 10% (0.67 g) in MeOH-EA (7.2 ml) was hydrogenated at rt for3 h. The reaction was filtered and the solvent removed to give 0.31 g ofthe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42 (quin, J=7.63Hz, 2H) 1.67 (quin, J=7.34 Hz, 2H) 2.45 (t, J=7.63 Hz, 2H) 3.95 (t,J=7.04 Hz, 2H) 6.64 (d, J=8.22 Hz, 2H) 6.86 (s, 1H) 6.94 (d, J=8.22 Hz,2H) 7.13 (s, 1H) 7.60 (s, 1H) 9.11 (s, 1H).

Step 3:(E)-4-((4-(4-(1H-imidazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-nitrostyryl)oxazole

This compound was prepared in a similar fashion as compound 1 step 5with (E)-4-(chloromethyl)-2-(2-fluoro-4-nitrostyryl)oxazole. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.49 (quin, J=7.40 Hz, 2H) 1.81 (quin, J=7.43 Hz,2H) 2.55 (t, J=7.63 Hz, 2H) 4.20 (t, J=7.04 Hz, 2H) 5.00 (s, 2H) 6.95(d, J=8.61 Hz, 2H) 7.11 (d, J=8.61 Hz, 2H) 7.47 (d, J=16.43 Hz, 1H) 7.61(d, J=16.82 Hz, 1H) 7.68 (s, 1H) 7.78 (s, 1H) 8.12 (dd, J=8.61, 2.35 Hz,1H) 8.18-8.27 (m, 2H) 8.29 (s, 1H) 9.11 (s, 1H).

Compound 100:(E)-4-((4-(4-(1H-imidazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

This compound was prepared as a TFA salt from the preparative HPLC(water-MeOH, 5% trifluoroacetic acid; 35-100%) in a similar fashion ascompound 99 with(E)-4-(chloromethyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.47 (quin, J=7.63 Hz, 2H) 1.78 (quin,J=7.34 Hz, 2H) 2.44-2.49 (m, 2H) 4.21 (t, J=7.24 Hz, 2H) 5.42 (s, 2H)6.59-6.68 (m, 2H) 6.95 (d, J=8.22 Hz, 2H) 7.37 (d, J=16.43 Hz, 1H) 7.59(d, J=16.43 Hz, 1H) 7.65 (d, J=8.22 Hz, 1H) 7.74-7.84 (m, 3H) 8.14 (t,J=7.83 Hz, 1H) 8.33 (s, 1H) 9.14 (br. s., 1H) 9.27 (s, 1H).

Compound 101:(E)-2-(2-(4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)-4-nitrostyryl)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazole

NaH 60% (0.017 g, 0.421 mmol) was added to a 0° C. solution of4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenol (0.080 g, 0.39 mmol) in DMF(0.876 ml). It was brought to rt 20 minutes then back to 0° C.(E)-4-(chloromethyl)-2-(2-fluoro-4-nitrostyryl)oxazole (0.104 g, 0.368mmol) in DMF (0.876 ml) was added to the solution and brought to rtovernight. The mixture was quenched with a NH₄Cl solution and extracted2× with EA. The combined organic solution was dried over Na₂SO₄,filtered and purified on ISCO using a RediSep® column (DCM-MeOH; 0-10%)to give 0.038 g of the bis-addition product. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.35-1.61 (m, 4H) 1.67-1.90 (m, 4H) 2.51-2.56 (m, 2H) 2.64 (t,J=7.63 Hz, 2H) 4.32-4.45 (m, 4H) 4.97 (s, 2H) 6.93 (d, J=8.61 Hz, 2H)7.09 (t, J=8.22 Hz, 4H) 7.29 (d, J=8.61 Hz, 2H) 7.44-7.53 (m, 2H) 7.70(d, J=3.91 Hz, 2H) 7.78 (d, J=16.43 Hz, 1H) 8.00 (dd, J=8.61, 2.35 Hz,1H) 8.11 (d, J=7.04 Hz, 2H) 8.21-8.29 (m, 2H).

Compound 102:(E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(pyridin-3-yl)butyl)phenoxy)methyl)oxazole

Step 1: 3-(4-(4-(benzyloxy)phenyl)but-1-yn-1-yl)pyridine

To a degassed mixture of 3-iodopyridine (0.109 g, 0.533 mmol) and1-(benzyloxy)-4-(but-3-yn-1-yl)benzene (J. Org. Chem. 2017, 82, 7070,(0.120 g, 0.508 mmol) in triethylamine (2.83 ml, 20.31 mmol) was addedcopper(I) iodide (2.90 mg, 0.015 mmol) and PdCl₂(PPh₃)₂(10.69 mg, 0.015mmol) and heated at 80° C. overnight. It was then cooled, diluted withEA, filtered, absorbed on SiO₂ and the solvent removed. Purification onISCO using a RediSep® column (Hx-EA; 0-50%) gave 0.117 g of the titlecompound.

Step 2: 4-(4-(pyridin-3-yl)butyl)phenol

A mixture of 3-(4-(4-(benzyloxy)phenyl)but-1-yn-1-yl)pyridine (0.117 g,0.37 mmol) and Pd 10% (0.023 g) in MeOH-EA (2.5 ml) was hydrogenated atrt overnight. The reaction was filtered and the solvent removed to give0.070 g of the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.58-1.71(m, 4H) 2.56 (t, J=7.24 Hz, 2H) 2.67 (t, J=7.43 Hz, 2H) 3.91 (s, 3H)4.58 (s, 1H) 6.74 (d, J=8.61 Hz, 2H) 7.02 (d, J=8.61 Hz, 2H) 7.31-7.38(m, 2H) 7.79-7.88 (m, 2H).

Step 3:(E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(pyridin-3-yl)butyl)phenoxy)methyl)oxazole

NaH (8.01 mg, 0.200 mmol) was added to 4-(4-(pyridin-3-yl)butyl)phenol(0.035 g, 0.154 mmol) in DMF (0.513 ml) followed by(E)-4-(chloromethyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole(0.052 g, 0.169 mmol) was added and let stirred overnight. The mixturewas quenched with a NH₄Cl solution and extracted 2× with EA. Thecombined organic solution was dried over Na₂SO₄, filtered and purifiedon ISCO using a RediSep® column (Hx-EA;15-100%) to give 0.036 g of thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.47-1.60 (m, 4H) 2.52(t, J=7.04 Hz, 2H) 2.59 (t, J=7.00 Hz, 1H) 4.97 (s, 2H) 6.92 (m, J=8.61Hz, 2H) 7.08 (m, J=8.61 Hz, 2H) 7.27 (dd, J=7.83, 4.70 Hz, 1H) 7.37 (d,J=16.43 Hz, 1H) 7.54-7.60 (m, 2H) 7.63 (d, J=8.61 Hz, 1H) 7.77 (d,J=10.56 Hz, 1H) 8.14 (t, J=7.43 Hz, 1H) 8.24 (s, 1H) 8.36 (d, J=4.70 Hz,1H) 8.39 (d, J=2.35 Hz, 1H).

Compound 103:(E)-2-(2-fluoro-4-nitrostyryl)-4-((4-(4-(pyridin-3-yl)butyl)phenoxy)methyl)oxazole

This compound was prepared in a similar fashion as compound 102 with(E)-4-(chloromethyl)-2-(2-fluoro-4-nitrostyryl)oxazole and4-(4-(pyridin-3-yl)butyl)phenol. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.47-1.61 (m, 4H) 2.53 (t, J=6.85 Hz, 2H) 2.59 (t, J=7.04 Hz, 2H) 4.98(s, 2H) 6.92 (m, J=8.61 Hz, 2H) 7.09 (m, J=8.22 Hz, 2H) 7.27 (dd,J=7.83, 4.70 Hz, 1H) 7.42-7.50 (m, 1H) 7.54-7.64 (m, 2H) 8.10 (dd,J=8.61, 1.96 Hz, 1H) 8.16-8.24 (m, 2H) 8.27 (s, 1H) 8.34-8.43 (m, 2H).

Compound 104:(E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(pyridin-4-yl)butyl)phenoxy)methyl)oxazole

Step 1: 4-(4-(pyridin-4-yl)butyl)phenol

This compound was prepared in a similar fashion as compound 102 step 1and 2 starting with 4-iodopyridine. 1H NMR (400 MHz, CDCl3) δ ppm1.58-1.71 (m, 4H) 2.56 (t, J=7.24 Hz, 2H) 2.67 (t, J=7.43 Hz, 2H) 3.91(s, 3H) 4.58 (s, 1H) 6.74 (d, J=8.61 Hz, 2H) 7.02 (d, J=8.61 Hz, 2H)7.31-7.38 (m, 2H) 7.79-7.88 (m, 2H).

Step 2:(E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(pyridin-4-yl)butyl)phenoxy)methyl)oxazole

This compound was prepared in a similar fashion as compound 102 step 3with (E)-4-(chloromethyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazoleand 4-(4-(pyridin-4-yl)butyl)phenol. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.46-1.61 (m, 4H) 2.52 (t, J=7.04 Hz, 2H) 2.59 (t, J=7.04 Hz, 2H) 4.97(s, 2H) 6.92 (m, J=8.61 Hz, 2H) 7.08 (m, J=8.22 Hz, 2H) 7.18 (d, J=5.48Hz, 2H) 7.37 (d, J=16.43 Hz, 1H) 7.57 (d, J=16.43 Hz, 1H) 7.62 (d,J=8.22 Hz, 1H) 7.76 (d, J=10.56 Hz, 1H) 8.14 (t, J=7.83 Hz, 1H) 8.24 (s,1H) 8.41 (d, J=5.48 Hz, 2H).

Compound 105:(E)-4-((4-(3-(1H-1,2,3-triazol-1-yl)propyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

This compound was prepared in a similar fashion as compound 50 with(E)-4-(chloromethyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole andwas further purified on preparative HPLC (water-MeOH, 5% trifluoroaceticacid; 40-100%). ¹H NMR (500 MHz, CDCL₃) δ ppm 1.59-1.67 (m, 2H) 1.94(dt, J=14.98, 7.33 Hz, 2H) 2.61 (t, J=7.57 Hz, 2H) 3.06-3.15 (m, 2H)3.16-3.24 (m, 2H) 4.40 (t, J=7.25 Hz, 2H) 4.95 (d, J=0.95 Hz, 2H)6.86-6.92 (m, 2H) 7.03-7.09 (m, 2H) 7.28-7.35 (m, 3H) 7.50 (s, 1H) 7.59(s, 1H) 7.70 (s, 1H). LRMS+H⁺: 473.3.

Compound 106:(E)-4-((4-(3-(1H-1,2,3-triazol-1-yl)propyl)phenoxy)methyl)-2-(2-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)styryl)oxazole

When preparing compound 105, a second adduct, compound 106 was alsoisolated:

¹H NMR (500 MHz, CDCl₃) δ ppm 2.19-2.31 (m, 2H) 2.62 (t, J=7.57 Hz, 2H)4.39 (t, J=7.09 Hz, 2H) 5.02 (s, 2H) 6.94 (m, J=8.51 Hz, 2H) 6.99 (d,J=15.76 Hz, 1H) 7.11 (m, J=8.51 Hz, 2H) 7.53 (br. s., 1H) 7.66 (s, 1H)7.70-7.77 (m, 2H) 7.85 (d, J=16.08 Hz, 1H) 7.90 (d, J=8.20 Hz, 1H)7.93-7.99 (m, 2H) 8.05 (s, 1H).

Compound 107:(E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(thiazol-2-yl)butyl)phenoxy)methyl)oxazole

Step 1: 1-(4-(benzyloxy)phenyl)but-3-yn-1-ol

To 4-(benzyloxy)benzaldehyde (4.0 g, 18.85 mmol) in THE (37.7 ml) wasadded 3-bromoprop-1-yne (3.16 ml, 28.3 mmol) and then activate zinc(3.70 g, 56.5 mmol) and the suspension stirred 24 h. It was then dilutedwith a NH4Cl solution, filtered and the solid washed with EA. Theorganic phase was separated, dried over Na₂SO₄ filtered and the solventremoved. Purification on ISCO using a RediSep® column (Hexane-EA; 0-40%)gave 4.8 g of the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.07 (t,J=2.74 Hz, 1H) 2.27 (d, J=3.52 Hz, 1H) 2.57-2.67 (m, 2H) 4.84 (td,J=6.36, 3.33 Hz, 1H) 5.07 (s, 2H) 6.87-7.00 (m, 2H) 7.29-7.35 (m, 3H)7.35-7.45 (m, 4H).

Step 2: 1-(benzyloxy)-4-(but-3-yn-1-yl)benzene

To a 0° C. solution of triethylsilane (6.08 ml, 38.0 mmol) and1-(4-(benzyloxy)phenyl)but-3-yn-1-ol (4.8 g, 19.02 mmol) in DCM (190 ml)was added BF₃·OEt₂ (4.82 ml, 38.0 mmol) and stirred for 2 h30. It wasdiluted with DCM and quenched with a NaHCO₃ solution. The organic phasewas separated, dried over Na₂SO₄ filtered and the solvent removed.Purification on ISCO using a RediSep® column (Hexane-EA; 0-50%) gave3.14 g of the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.98 (t,J=2.54 Hz, 1H) 2.46 (td, J=7.53, 2.54 Hz, 2H) 2.80 (t, J=7.43 Hz, 2H)5.06 (s, 2H) 6.87-6.96 (m, 2H) 7.13-7.18 (m, 2H) 7.30-7.36 (m, 1H) 7.39(t, J=7.24 Hz, 2H) 7.42-7.48 (m, 2H)

Step 3: 2-(4-(4-(benzyloxy)phenyl)but-1-yn-1-yl)thiazole

This compound was prepared in a similar fashion as compound 102, step 1with the previous alkyne and 2-bromothiazole. LRMS+H⁺: 320.0.

Step 4: 4-(4-(thiazol-2-yl)butyl)phenol

The previous alkyne was hydrogenated with Pd/C in MeOH-EA at 1atmosphere and the residue then deprotected by the addition of 2.8equivalent BCl₃ (1.0M) to a −78° C. solution of the residue (0.05M) inDCM containing 5.0 equivalent of pentamethyl benzene for 1 h. Themixture was quenched with a NaHCO₃ solution and brought to rt. Thephases were separated and the aqueous extracted with DCM and combined.It was then dried over Na₂SO₄ filtered and the solvent removed.Purification on ISCO using a RediSep® column (Hexane-EA; 0-70%) to givethe title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.62-1.72 (m, 2H) 1.83(quin, J=7.63 Hz, 2H) 2.58 (t, J=7.63 Hz, 2H) 3.05 (t, J=7.43 Hz,2H)₅.41 (br. s., 1H) 6.65-6.77 (m, 2H) 7.01 (m, J=8.61 Hz, 2H) 7.18 (d,J=3.13 Hz, 1H) 7.67 (d, J=3.52 Hz, 1H).

Step 5:(E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(thiazol-2-yl)butyl)phenoxy)methyl)oxazole

This compound was prepared in a similar fashion as compound 102, step 3with the previous phenol and the corresponding oxazol. ¹H NMR (400 MHz,DMSO-d6) δ ppm 1.58 (m, J=7.04 Hz, 2H) 1.64-1.74 (m, 2H) 2.53 (t, J=7.43Hz, 2H) 2.98 (t, J=7.43 Hz, 2H) 4.97 (s, 2H) 6.92 (m, J=8.61 Hz, 2H)7.09 (m, J=8.61 Hz, 2H) 7.37 (d, J=16.80 Hz, 1H) 7.52 (d, J=3.52 Hz, 1H)7.57 (d, J=16.80 Hz, 1H) 7.62 (br. d, J=8.50 Hz, 1H) 7.65 (d, J=3.13 Hz,1H) 7.76 (br. d, J=11.00 Hz, 1H) 8.14 (t, J=8.00 Hz, 1H) 8.24 (s, 1H).LRMS+H⁺=503.1.

Compound 108:(E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(pyrimidin-5-yl)butyl)phenoxy)methyl)oxazole

Step 1: 2-(4-(4-(benzyloxy)phenyl)but-1-yn-1-yl)pyrimidine

This compound was prepared in a similar fashion as compound 107, step 3with 2-bromopyrimidine. LRMS+H⁺=315.0.

Step 2: 4-(4-(pyrimidin-5-yl)butyl)phenol

This compound was prepared in a similar fashion as compound 107, step 4.LRMS+H⁺=229.2.

Step 3:(E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(pyrimidin-5-yl)butyl)phenoxy)methyl)oxazole

This compound was prepared in a similar fashion as compound 102, step 3with the previous phenol. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (quint,J=7.40 Hz, 2H) 1.73 (quint, J=7.60 Hz, 2H) 2.53 (t, J=7.63 Hz, 2H) 2.85(t, J=7.43 Hz, 2H) 4.97 (s, 2H) 6.92 (m, J=8.61 Hz, 2H) 7.08 (m, J=8.22Hz, 2H) 7.29 (t, J=4.89 Hz, 1H) 7.37 (d, J=16.43 Hz, 1H) 7.57 (d,J=16.82 Hz, 1H) 7.62 (d, J=8.22 Hz, 1H) 7.76 (d, J=10.96 Hz, 1H) 8.14(t, J=7.63 Hz, 1H) 8.24 (s, 1H) 8.68 (d, J=4.70 Hz, 2H). LRMS+H⁺=498.2.

Compound 109:(E)-4-((4-(3-(1H-1,2,3-triazol-1-yl)propoxy)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

Step 1: 3-(4-methoxyphenoxy)propyl methanesulfonate

This compound was prepared in a similar fashion as compound 1, step 1starting with 3-(4-methoxyphenoxy)propan-1-ol (1.045 g, 5.73 mmol). ¹HNMR (400 MHz, CDCl₃) δ ppm 2.20 (t, J=6.06 Hz, 2H) 2.99 (s, 3H) 3.77 (s,3H) 4.04 (t, J=5.87 Hz, 2H) 4.44 (t, J=6.26 Hz, 2H) 6.83 (s, 4H).

Step 2: 1-(3-azidopropoxy)-4-methoxybenzene

Sodium azide (0.225 g, 3.46 mmol) was added to3-(4-methoxyphenoxy)propyl methanesulfonate (0.6 g, 2.305 mmol) inN,N-dimethylformamide (1 ml). The reaction mixture was heated to 50° C.for 16 hr, then cooled to 20° C. and quenched with water (3 ml). Thereaction mixture was extracted with Et₂O (3×10 ml) and the organic layerwas washed with water (10 ml) and brine (10 ml), dried over MgSO₄,filtered and concentrated to give title compound (0.46 g, 96%) as anoil. ¹H NMR (400 MHz, MeOH-d4) δ ppm 2.03 (t, J=6.26 Hz, 2H) 3.51 (t,J=6.65 Hz, 2H) 3.77 (s, 2H) 4.00 (t, J=5.87 Hz, 2H) 6.84 (s, 3H).

Step 3: 1-(3-(4-methoxyphenoxy)propyl)-1H-1,2,3-triazole

A mixture of 1-(3-azidopropoxy)-4-methoxybenzene (0.3 g, 1.45 mmol) andvinyl acetate (3.96 ml, 43.4 mmol) in a microwave tube was heated to120° C. for 21 h. The mixture was concentrated to dryness and theresidue was purified on ISCO using a RediSep® column (DCM to 40% AcOEtin DCM) to give title compound (0.27 g, 80% yield) as a colorless oil.¹H NMR (400 MHz, CDCl₃) δ ppm 2.38 (quin, J=6.26 Hz, 2H) 3.77 (s, 2H)3.89 (t, J=5.87 Hz, 2H) 4.62 (t, J=6.85 Hz, 2H) 6.76-6.88 (m, 3H) 7.54(s, 1H) 7.69 (s, 1H).

Step 4: 4-(3-(1H-1,2,3-triazol-1-yl)propoxy)phenol

This compound was prepared in a similar fashion as compound 1, step 4.¹H NMR (400 MHz, CDCl₃) δ ppm 2.32 (t, J=5.87 Hz, 2H) 3.83 (t, J=5.67Hz, 2H) 4.58 (t, J=6.85 Hz, 2H) 6.71 (d, J=1.57 Hz, 4H) 7.55 (s, 1H)7.64 (s, 1H).

Step 5:(E)-4-((4-(3-(1H-1,2,3-triazol-1-yl)propoxy)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl) oxazole

This compound was prepared in a similar fashion as compound 1, step 5.¹H NMR (400 MHz, CDCl₃) δ ppm 2.39 (t, J=6.06 Hz, 2H) 3.90 (t, J=5.67Hz, 2H) 4.62 (t, J=6.85 Hz, 2H) 4.99 (s, 2H) 6.76-6.86 (m, 2H) 6.88-6.99(m, 2H) 7.13 (d, J=16.82 Hz, 1H) 7.33-7.48 (m, 2H) 7.55 (s, 1H)7.59-7.72 (m, 3H). LRMS+H⁺=489.1.

Compound 110:(E)-4-((4-(4-(2H-tetrazol-2-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

Step 1: 2-(4-(4-methoxyphenyl)butyl)-2H-tetrazole

This compound was isolated as a regioisomer in the preparation ofcompound 90. LRMS+H⁺=233.1.

Step 2: 4-(4-(2H-tetrazol-2-yl)butyl)phenoI

This compound was prepared in a similar fashion as compound 1, step 3.¹H NMR (400 MHz, CDCl₃) δ ppm 1.58-1.68 (m, 2H) 1.92-2.11 (m, 2H)2.56-2.63 (m, 2H) 4.78 (s, 0H) 4.65 (t, J=7.04 Hz, 2H) 6.69-6.80 (m, 2H)7.01 (m, J=8.61 Hz, 2H) 8.49 (s, 1H).

Step 3:(E)-4-((4-(4-(2H-tetrazol-2-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

This compound was prepared in a similar fashion as compound 1, step 5.¹H NMR (400 MHz, CDCl₃) δ ppm 1.63 (t, J=7.63 Hz, 2H) 1.95-2.15 (m, 2H)2.61 (t, J=7.43 Hz, 2H) 4.65 (t, J=7.04 Hz, 2H) 5.02 (s, 2H) 6.91 (d,J=8.22 Hz, 2H) 7.03-7.19 (m, 3H) 7.33-7.49 (m, 2H) 7.57-7.76 (m, 3H)8.49 (s, 1H). HRMS+H⁺: 488.1747.

Compound 111:4-((E)-4-(4-(1H-1,2,3-triazol-1-yl)butyl)styryl)-2-((E)-2-fluoro-4-(trifluoromethyl)styryl)oxazole

Step 1:(E)-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methyl)triphenylphosphoniumchloride

A mixture of triphenylphosphine (0.113 μg, 0.429 μmmol) and(E)-4-(chloromethyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole(0.125 g, 0.409 mmol) in ACN (4.09 ml) was heated to 95° C. overnight.The solvent was removed and the residue taken in EA and the solventremoved again. A solid was obtained and stirred in ethyl ether with 2-3%EA. The solid was filtered and dried under high vacuum to give 0.092 gof the title compound. LRMS+H⁺: 532.2.

Step 2: 4-(4-hydroxybut-1-yn-1-yl)benzaldehyde

This compound was prepared in a similar fashion as compound 102, step 1with 4-bromobenzaldehyde.

Step 3: 4-(4-hydroxybutyl)benzaldehyde

A Mixture of the previous aldehyde (0.400 g, 2.3 mmol) and Pd/C (0.040g) in EA (23 ml) was hydrogenated until completion. The mixture wasfiltered and the solvent removed. Purification on ISCO using a RediSep®column (Hx-EA; 0-60%) gave 0.147 g of the title compound. ¹H NMR (400MHz, CDCl₃) δ ppm 1.59-1.66 (m, 2H) 1.68-1.80 (m, 2H) 2.73 (t, J=7.63Hz, 2H) 3.68 (t, J=6.26 Hz, 2H) 7.35 (m, J=7.83 Hz, 2H) 7.80 (m, J=8.22Hz, 2H) 9.97 (s, 1H).

Step 4: 4-(4-(1H-1,2,3-triazol-1-yl)butyl)benzaldehyde

This compound was prepared in a similar fashion as compound 109, step 1,2 and 3 from the previous alcohol and used directly for the next step.

Step 5:4-((E)-4-(4-(1H-1,2,3-triazol-1-yl)butyl)styryl)-2-((E)-2-fluoro-4-(trifluoromethyl)styryl)oxazole

To a solution of(E)-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methyl)triphenylphosphoniumchloride (0.092 g, 0.161 mmol) and4-(4-(1H-1,2,3-triazol-1-yl)butyl)benzaldehyde (0.037 g, 0.161 mmol) inEtOH (0.538 ml) at rt was added solid potassium t-butoxide (0.020 g,0.178 mmol). Let go for 4 h. The reaction was quenched with water anddiluted with EA. The layers were separated and the aqueous extractedwith EA, combined, Na₂SO₄ dried, filtered and the solvent removed. Theresidues was absorbed on SiO2 and purified on ISCO using a RediSep®column (Hexane-EA; 0-100%) to give 0.041 g of a mixture of cis andtrans. 6 mg of the mixture was taken in a 5% solution of iodine intoluene and heated at 100 C overnight. The solvent was removed and theresidue taken in EA and solvent removed again to give 4.5 mg of thetrans adduct. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (quint, J=7.40 Hz,2H) 1.73 (quint, J=7.60 Hz, 2H) 2.53 (t, J=7.63 Hz, 2H) 2.85 (t, J=7.43Hz, 2H) 4.97 (s, 2H) 6.92 (m, J=8.61 Hz, 2H) 7.08 (m, J=8.22 Hz, 2H)7.29 (t, J=4.89 Hz, 1H) 7.37 (d, J=16.43 Hz, 1H) 7.57 (d, J=16.82 Hz,1H) 7.62 (d, J=8.22 Hz, 1H) 7.76 (d, J=10.96 Hz, 1H) 8.14 (t, J=7.63 Hz,1H) 8.24 (s, 1H) 8.68 (d, J=4.70 Hz, 2H). LRMS+H⁺=483.1.

Compound 112:4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(5-fluorobenzofuran-2-yl)oxazole

Step 1: 5-fluorobenzofuran-2-carboxamide

This compound was prepared in a similar fashion as compound 76 step 4using 5-fluorobenzofuran-2-carboxylic acid. ¹H NMR (400 MHz, DMSO-d₆) δppm 8.14 (br. s., 1H), 7.72 (br. s., 1H), 7.67 (dd, J=9.0, 4.3 Hz, 1H),7.59 (dd, J=8.6, 2.7 Hz, 1H), 7.52 (s, 1H), 7.30 (td, J=9.2, 2.7 Hz,1H).

Step 2: 4-(chloromethyl)-2-(5-fluorobenzofuran-2-yl)oxazole

This compound was prepared in a similar fashion as compound 61 step 3using the previous intermediate. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.39(s, 1H), 7.78 (dd, J=9.0, 4.3 Hz, 1H), 7.65 (s, 1H), 7.59 (dd, J=8.8,2.5 Hz, 1H), 7.33 (td, J=9.4, 2.7 Hz, 1H), 4.78 (s, 2H).

Step 3:4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(5-fluorobenzofuran-2-yl)oxazole

This compound was prepared according to compound 1 step 5. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.40 (s, 1H), 8.11 (s, 1H), 7.77 (dd, J=9.0, 4.3 Hz,1H), 7.70 (s, 1H), 7.63 (s, 1H), 7.58 (dd, J=8.8, 2.5 Hz, 1H), 7.32 (td,J=9.2, 2.7 Hz, 1H), 7.07-7.14 (m, J=8.6 Hz, 2H), 6.91-7.00 (m, J=8.6 Hz,2H), 5.05 (s, 2H), 4.39 (t, J=7.0 Hz, 2H), 2.54 (t, J=7.8 Hz, 2H), 1.81(quin, J=7.3 Hz, 2H), 1.48 (quin, J=7.6 Hz, 2H).

Compound 113:4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(5-fluorobenzo[b]thiophen-2-yl)oxazole

Step 1: 5-Fluorobenzo[b]Thiophene-2-Carboxamide

This compound was prepared in a similar fashion as compound 76 step 4using 5-fluorobenzo[b]thiophene-2-carboxylic acid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.26 (br. s., 1H), 8.00-8.09 (m, 2H), 7.77 (dd, J=9.8,2.7 Hz, 1H), 7.65 (br. s., 1H), 7.34 (td, J=9.0, 2.7 Hz, 1H).

Step 2: 4-(chloromethyl)-2-(5-fluorobenzo[b]thiophen-2-yl)oxazole

This compound was prepared in a similar fashion as compound 61 step 3using the previous intermediate. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.34(s, 1H), 8.13 (dd, J=8.8, 4.9 Hz, 1H), 8.08 (s, 1H), 7.81 (dd, J=9.6,2.5 Hz, 1H), 7.38 (td, J=9.0, 2.3 Hz, 1H), 4.76 (s, 2H).

Step 3:4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(5-fluorobenzo[b]thiophen-2-yl)oxazole

This compound was prepared according to compound 1 step 5. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.36 (s, 1H), 8.09-8.15 (m, 2H), 8.06 (s, 1H), 7.81(dd, J=9.6, 2.5 Hz, 1H), 7.70 (s, 1H), 7.37 (td, J=9.0, 2.7 Hz, 1H),7.07-7.14 (m, J=8.6 Hz, 2H), 6.92-6.99 (m, J=8.6 Hz, 2H), 5.03 (s, 2H),4.39 (t, J=7.0 Hz, 2H), 2.54 (t, J=7.4 Hz, 2H), 1.81 (quin, J=7.3 Hz,2H), 1.48 (quin, J=7.5 Hz, 2H).

Compound 114: ethyl(E)-1-(4-(4-((2-(4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)-1H-1,2,3-triazole-4-carboxylate

This compound was prepared in a similar fashion as compound 4 with(E)-4((4-(4-azidobutyl)phenoxy)methyl)-2-(4-(trifluoromethyl)styryl)oxazoleand ethyl propiolate. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29 (t, J=7.04Hz, 3H) 1.47 (quin, J=7.60 Hz, 2H) 1.84 (quin, J=7.40 Hz, 2H) 2.51-2.57(m, 2H) 4.30 (q, J=7.17 Hz, 2H) 4.43 (t, J=7.04 Hz, 2H) 4.98 (s, 2H)6.94 (d, J=8.61 Hz, 2H) 7.10 (d, J=8.61 Hz, 2H) 7.34 (d, J=16.43 Hz, 1H)7.61 (d, J=16.43 Hz, 1H) 7.76 (m, J=8.22 Hz, 2H) 7.95 (d, J=8.22 Hz, 2H)8.23 (s, 1H) 8.78 (s, 1H). LRMS+H⁺=541.1.

Compound 115:(E)-4-((4-((2-(1H-1,2,3-triazol-1-yl)ethoxy)methyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

Step 1: (4-(chloromethyl)phenoxy)triisopropylsilane

To a solution of (4-((triisopropylsilyl)oxy)phenyl)methanol (1.5 g, 5.35mmol) in DCM (10.70 ml) was added thionyl chloride (0.624 ml, 8.56 mmol)dropwise at 0° C. After the addition the ice bath was removed and thereaction mixture was stirred at room temperature for 2 h. The mixturewas diluted with DCM (20 ml), washed with water (3×10 ml), dried andconcentrated. The residue was purified using ISCO column (Hx to 20%AcOEt) to give title compound (1.3 g, 81% yield). ¹H NMR (400 MHz,CDCl₃) δ ppm 1.09 (d, J=7.04 Hz, 18H) 1.19-1.30 (m, 3H) 4.55 (s, 2H)6.84 (d, J=8.61 Hz, 2H) 7.23 (d, J=8.61 Hz, 2H).

Step 2: 4-((2-azidoethoxy)methyl)phenol

Sodium hydride (0.039 g, 1.606 mmol) was added to a cold solution of2-azidoethanol (0.140 g, 1.606 mmol) in DMF (3 ml), followed by Bu4NI(9.42 mg, 0.067 mmol). After 15 min,(4-(chloromethyl)phenoxy)triisopropylsilane (0.4 g, 1.3 mmol) was addedand the reaction mixture was stirred overnight. The mixture was dilutedwith AcOEt (20 ml), filtered through a pad of celite and the filtratewas concentrated to dryness. The residue was purified on ISCO using aRediSep® column (DCM/EA; 0-40%) to give 0.060 g (23%) of the titlecompound. 1H NMR (400 MHz, CDCl3) δ ppm 3.39 (t, J=5.09 Hz, 2H) 3.63 (t,J=5.09 Hz, 2H) 3.81 (s, 2H) 4.51 (s, 2H) 6.89 (d, J=8.61 Hz, 1H) 7.28(d, J=8.61 Hz, 1H).

Step 3: 4-((2-(1H-1,2,3-triazol-1-yl)ethoxy)methyl)phenol

A mixture of 4-((2-azidoethoxy)methyl)phenol (0.06 g, 0.311 mmol) invinyl acetate (0.851 ml, 9.32 mmol) was heated to 120° C. for 21 h in amicrowave tube. The mixture was concentrated to dryness under highvacuum to give desired 4-((2-(1H-1,2,3-triazol-1-yl)ethoxy)methyl)phenol(64 mg, 0.29 mmol, 94% yield) as a colorless oil, which was pure enoughfor next reaction without further purification. ¹H NMR (400 MHz, CDCl₃)δ ppm 3.82 (t, J=5.09 Hz, 2H) 4.41 (s, 2H) 4.58 (t, J=5.09 Hz, 2H) 5.09(s, 1H) 6.80 (m, J=8.22 Hz, 2H) 7.11 (m, J=8.22 Hz, 2H) 7.69 (d, J=4.30Hz, 2H).

Step 4:(E)-4-((4-((2-(1H-1,2,3-triazol-1-yl)ethoxy)methyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

This compound was prepared in a similar fashion as compound 32 from theprevious phenol and(E)-4-(chloromethyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole. ¹HNMR (400 MHz, CDCl₃) δ ppm 3.83 (t, J=5.09 Hz, 2H) 4.44 (s, 2H) 4.58 (t,J=5.09 Hz, 2H) 5.04 (s, 2H) 6.96 (d, J=8.61 Hz, 2H) 7.09-7.21 (m, 3H)7.38 (d, J=10.56 Hz, 1H) 7.44 (d, J=8.22 Hz, 1H) 7.58-7.75 (m, 5H).LRMS+H⁺=489.2.

Compound 116:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-chloro-2-fluorostyryl)oxazole

Step 1: (E)-2-(4-chloro-2-fluorostyryl)-4-(chloromethyl)oxazole

This compound was prepared in a similar fashion as compound 3A/B step 1and 2 from the corresponding (E)-3-(4-chloro-2-fluorophenyl)acrylicacid. ¹H NMR (DMSO-d₆) δ: 8.21 (s, 1H), 7.96 (t, J=8.4 Hz, 1H),7.48-7.58 (m, 2H), 7.37 (dd, J=8.6, 1.6 Hz, 1H), 7.25 (d, J=16.8 Hz,1H), 4.71 (s, 2H).

Step 2:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4-chloro-2-fluorostyryl)oxazole

This compound was prepared in a similar fashion as compound 32 step 2from the previous chloride and the corresponding phenol. ¹H NMR(DMSO-d₆) δ: 8.22 (s, 1H), 8.11 (s, 1H), 7.95 (t, J=8.4 Hz, 1H), 7.70(s, 1H), 7.48-7.58 (m, 2H), 7.37 (d, J=8.6 Hz, 1H), 7.25 (d, J=16.8 Hz,1H), 7.05-7.14 (d, J=8.6 Hz, 2H), 6.90-6.98 (d, J=8.2 Hz, 2H), 4.98 (s,2H), 4.39 (t, J=7.0 Hz, 2H), 2.52-2.58 (m, 2H), 1.81 (quin, J=7.2 Hz,2H), 1.48 (quin, J=7.5 Hz, 2H). LRMS+H⁺=453.1.

Compound 117:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-chloro-4-fluorostyryl)oxazole

Step 1: (E)-2-(2-chloro-4-fluorostyryl)-4-(chloromethyl)oxazole

This compound was prepared in a similar fashion as compound 3A/B step 1and 2 from the corresponding (E)-3-(2-chloro-4-fluorophenyl)acrylicacid. ¹H NMR (DMSO-d₆) δ: 8.21 (s, 1H), 8.09 (dd, J=8.6, 6.3 Hz, 1H),7.72 (d, J=16.0 Hz, 1H), 7.56 (dd, J=8.8, 2.5 Hz, 1H), 7.32 (td, J=8.6,2.7 Hz, 1H), 7.25 (d, J=16.0 Hz, 1H), 4.72 (s, 2H).

Step 2:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-chloro-4-fluorostyryl)oxazole

This compound was prepared in a similar fashion as compound 32 step 2from the previous chloride and the corresponding phenol. ¹H NMR(DMSO-d₆) δ: 8.22 (s, 1H), 8.04-8.13 (m, 2H), 7.67-7.76 (m, 2H), 7.56(dd, J=8.6, 2.3 Hz, 1H), 7.32 (td, J=8.5, 2.5 Hz, 1H), 7.25 (d, J=16.4Hz, 1H), 7.06-7.13 (d, J=8.6 Hz, 2H), 6.90-6.97 (d, J=8.6 Hz, 2H), 4.98(s, 2H), 4.39 (t, J=7.0 Hz, 2H), 2.52-2.58 (m, 2H), 1.81 (quin, J=7.3Hz, 2H), 1.48 (quin, J=7.5 Hz, 2H). LRMS+H⁺=453.1. LRMS+H⁺=453.1.

Compound 118:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-chlorostyryl)oxazole

Step 1: (E)-4-(chloromethyl)-2-(2-chlorostyryl)oxazole

This compound was prepared in a similar fashion as compound 3A/B step 1and 2 from the corresponding (E)-3-(2-chlorophenyl)acrylic acid. ¹H NMR(DMSO-d₆) δ: 8.21 (s, 1H), 8.09 (dd, J=8.6, 6.3 Hz, 1H), 7.72 (d, J=16.0Hz, 1H), 7.56 (dd, J=8.8, 2.5 Hz, 1H), 7.32 (td, J=8.6, 2.7 Hz, 1H),7.25 (d, J=16.0 Hz, 1H), 4.72 (s, 2H).

Step 2:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-chlorostyryl)oxazole

This compound was prepared in a similar fashion as compound 32 step 2from the previous chloride and the corresponding phenol. ¹H NMR(DMSO-d₆) δ: 8.23 (s, 1H), 8.11 (s, 1H), 7.98-8.05 (m, 1H), 7.78 (d,J=16.4 Hz, 1H), 7.70 (s, 1H), 7.50-7.58 (m, 1H), 7.36-7.44 (m, 2H), 7.27(d, J=16.4 Hz, 1H), 7.05-7.14 (d, J=8.6 Hz, 2H), 6.91-6.98 (d, J=8.6 Hz,2H), 4.99 (s, 2H), 4.39 (t, J=7.0 Hz, 2H), 2.52-2.58 (m, 2H), 1.81(quin, J=7.3 Hz, 2H), 1.48 (quin, J=7.6 Hz, 2H). LRMS+H⁺=435.1.

Compound 119:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2,4-dichlorostyryl)oxazole

Step 1: (E)-4-(chloromethyl)-2-(2,4-dichlorostyryl)oxazole

This compound was prepared in a similar fashion as compound 3A/B step 1and 2 from the corresponding (E)-3-(2,4-dichlorophenyl)acrylic acid. ¹HNMR (DMSO-d₆) δ: 8.22 (s, 1H), 8.05 (d, J=8.6 Hz, 1H), 7.67-7.76 (m,2H), 7.50 (dd, J=8.6, 2.3 Hz, 1H), 7.30 (d, J=16.4 Hz, 1H), 4.72 (s,2H).

Step 2:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2,4-dichlorostyryl)oxazole

This compound was prepared in a similar fashion as compound 32 step 2from the previous chloride and the corresponding phenol. ¹H NMR(DMSO-d₆) δ: 8.24 (s, 1H), 8.11 (s, 1H), 8.05 (d, J=8.6 Hz, 1H),7.67-7.75 (m, 3H), 7.50 (dd, J=8.6, 2.0 Hz, 1H), 7.31 (d, J=16.4 Hz,1H), 7.06-7.13 (d, J=8.6 Hz, 2H), 6.90-6.98 (d, J=8.2 Hz, 2H), 4.99 (s,2H), 4.39 (t, J=7.0 Hz, 2H), 2.52-2.57 (m, 2H), 1.80 (quin, J=7.2 Hz,2H), 1.47 (quin, J=7.6 Hz, 2H). LRMS+H⁺=469.1.

Compound 120:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(3,4,5-trifluorostyryl)oxazole

Step 1: (E)-4-(chloromethyl)-2-(3,4,5-trifluorostyryl)oxazole

This compound was prepared in a similar fashion as compound 58 step 1-3from the corresponding aldehyde. ¹H NMR (DMSO-d₆) δ: 7.48-7.63 (m, 3H),7.36 (d, J=15.7 Hz, 1H), 7.21 (br. s., 1H), 6.64 (d, J=15.7 Hz, 1H).

Step 2:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(3,4,5-trifluorostyryl)oxazole

This compound was prepared in a similar fashion as compound 32 step 2from the previous chloride and the corresponding phenol. ¹H NMR(DMSO-d₆) δ: 8.22 (s, 1H), 8.11 (s, 1H), 7.80 (dd, J=9.0, 7.0 Hz, 2H),7.70 (s, 1H), 7.49 (d, J=16.4 Hz, 1H), 7.30 (d, J=16.4 Hz, 1H),7.05-7.14 (m, J=8.6 Hz, 2H), 6.89-6.98 (m, J=8.2 Hz, 2H), 4.97 (s, 2H),4.39 (t, J=7.0 Hz, 2H), 2.52-2.58 (m, 2H), 1.81 (quin, J=7.2 Hz, 2H),1.48 (quin, J=7.6 Hz, 2H). LRMS+H⁺=455.2.

Compound 121:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(3,4-difluorostyryl)oxazole

Step 1: (E)-4-(chloromethyl)-2-(3,4-difluorostyryl)oxazole

This compound was prepared in a similar fashion as compound 58 step 1-3from the corresponding aldehyde. ¹H NMR (DMSO-d₆) δ: 8.18 (s, 1H), 7.93(ddd, J=12.1, 7.8, 2.0 Hz, 1H), 7.56-7.62 (m, 1H), 7.42-7.56 (m, 2H),7.21 (d, J=16.4 Hz, 1H), 4.70 (s, 2H).

Step 2:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(3,4-difluorostyryl)oxazole

This compound was prepared in a similar fashion as compound 32 step 2from the previous chloride and the corresponding phenol. ¹H NMR(DMSO-d₆) δ: 8.20 (s, 1H), 8.11 (d, J=0.8 Hz, 1H), 7.92 (ddd, J=12.1,7.8, 2.0 Hz, 1H), 7.70 (d, J=0.8 Hz, 1H), 7.55-7.62 (m, 1H), 7.41-7.55(m, 2H), 7.22 (d, J=16.4 Hz, 1H), 7.05-7.13 (d, J=8.6 Hz, 2H), 6.88-6.98(m, 2H), 4.97 (s, 2H), 4.39 (t, J=7.0 Hz, 2H), 2.52-2.57 (m, 2H), 1.81(quin, J=7.3 Hz, 2H), 1.42-1.54 (m, 2H). LRMS+H⁺=437.2.

Compound 122:(E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)-3-fluorobenzonitrile

Step 1:(E)-4-(2-(4-(chloromethyl)oxazol-2-yl)vinyl)-3-fluorobenzonitrile

This compound was prepared in a similar fashion as compound 58 step 1-3from the corresponding aldehyde. ¹H NMR (DMSO-d₆) δ: 8.25 (s, 1H), 8.14(t, J=7.8 Hz, 1H), 7.96 (dd, J=11.0, 1.2 Hz, 1H), 7.77 (d, J=9.0 Hz,1H), 7.58 (d, J=16.8 Hz, 1H), 7.42 (d, J=16.8 Hz, 1H), 4.72 (s, 2H).

Step 2:(E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)-3-fluorobenzonitrile

This compound was prepared in a similar fashion as compound 32 step 2from the previous chloride and the corresponding phenol. ¹H NMR(DMSO-d₆) δ: 8.27 (s, 1H), 8.14 (t, J=8.0 Hz, 1H), 8.11 (d, J=0.8 Hz,1H), 7.95 (dd, J=10.6, 1.2 Hz, 1H), 7.76 (dd, J=8.2, 1.2 Hz, 1H),7.68-7.72 (m, 1H), 7.57 (d, J=16.8 Hz, 1H), 7.42 (d, J=16.8 Hz, 1H),7.06-7.12 (d, J=8.6 Hz, 2H), 6.90-6.97 (m, 2H), 4.99 (s, 2H), 4.39 (t,J=7.0 Hz, 2H), 2.52-2.56 (m, 2H), 1.81 (quin, J=7.2 Hz, 2H), 1.41-1.54(m, 2H). LRMS+H⁺=444.2.

Compound 123:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(methylsulfonyl)styryl)oxazole

Step 1:(E)-4-(chloromethyl)-2-(2-fluoro-4-(methylsulfonyl)styryl)oxazole

This compound was prepared in a similar fashion as compound 58 step 1-3from the corresponding aldehyde. ¹H NMR (DMSO-d₆) δ: 8.26 (s, 1H), 8.22(t, J=7.6 Hz, 1H), 7.86 (dd, J=10.0, 1.4 Hz, 1H), 7.80 (dd, J=8.0, 1.4Hz, 1H), 7.61 (d, J=16.4 Hz, 1H), 7.42 (d, J=16.8 Hz, 1H), 4.73 (s, 2H),3.30 (s, 3H).

Step 2:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(methylsulfonyl)styryl)oxazole

This compound was prepared in a similar fashion as compound 32 step 2from the previous chloride and the corresponding phenol. ¹H NMR(DMSO-d₆) δ: 8.27 (s, 1H), 8.22 (t, J=7.8 Hz, 1H), 8.08-8.13 (m, 1H),7.86 (dd, J=10.0, 1.8 Hz, 1H), 7.80 (dd, J=8.2, 1.6 Hz, 1H), 7.70 (d,J=0.8 Hz, 1H), 7.60 (d, J=16.8 Hz, 1H), 7.43 (d, J=16.4 Hz, 1H),7.05-7.13 (d, J=8.6 Hz, 2H), 6.90-6.98 (m, 2H), 5.00 (s, 2H), 4.39 (t,J=7.0 Hz, 2H), 3.30 (s, 3H), 2.52-2.57 (m, 2H), 1.81 (quin, J=7.2 Hz,2H), 1.48 (quin, J=7.6 Hz, 2H). LRMS+H⁺=497.2.

Compound 124:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethoxy)styryl)oxazole

Step 1:(E)-4-(chloromethyl)-2-(2-fluoro-4-(trifluoromethoxy)styryl)oxazole

This compound was prepared in a similar fashion as compound 58 step 1-3from the corresponding aldehyde. ¹H NMR (DMSO-d₆) δ: 8.22 (s, 1H), 8.07(t, J=8.6 Hz, 1H), 7.55 (d, J=16.4 Hz, 1H), 7.50 (d, J=12.5 Hz, 1H),7.32 (d, J=9.0 Hz, 1H), 7.27 (d, J=16.8 Hz, 1H), 4.71 (s, 2H).

Step 2:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethoxy)styryl)oxazole

This compound was prepared in a similar fashion as compound 32 step 2from the previous chloride and the corresponding phenol. ¹H NMR(DMSO-d₆) δ: 8.23 (s, 1H), 8.09-8.13 (m, 1H), 8.06 (t, J=8.8 Hz, 1H),7.67-7.73 (m, 1H), 7.46-7.59 (m, 2H), 7.23-7.35 (m, 2H), 7.05-7.14 (d,J=8.6 Hz, 2H), 6.89-6.98 (d, 2H), 4.98 (s, 2H), 4.39 (t, J=7.0 Hz, 2H),2.52-2.57 (m, 2H), 1.81 (quin, J=7.3 Hz, 2H), 1.42-1.54 (m, 2H).LRMS+H⁺=503.1.

Compound 125: methyl(E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)-3-fluorobenzoate

Step 1: methyl(E)-4-(2-(4-(chloromethyl)oxazol-2-yl)vinyl)-3-fluorobenzoate

This compound was prepared in a similar fashion as compound 58 step 1-3from the corresponding aldehyde. ¹H NMR (DMSO-d₆) δ: 8.24 (s, 1H), 8.08(t, J=7.8 Hz, 1H), 7.73-7.84 (m, 2H), 7.60 (d, J=16.4 Hz, 1H), 7.37 (d,J=16.8 Hz, 1H), 4.72 (s, 2H), 3.88 (s, 3H).

Step 2: methyl(E)-4-(2-(4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)oxazol-2-yl)vinyl)-3-fluorobenzoate

This compound was prepared in a similar fashion as compound 32 step 2from the previous chloride and the corresponding phenol. ¹H NMR(DMSO-d₆) δ: 8.26 (s, 1H), 8.04-8.12 (m, 2H), 7.82 (dd, J=8.0, 1.4 Hz,1H), 7.77 (dd, J=11.2, 1.4 Hz, 1H), 7.70 (s, 1H), 7.59 (d, J=16.4 Hz,1H), 7.38 (d, J=16.4 Hz, 1H), 7.06-7.12 (d, J=8.2 Hz, 2H), 6.90-6.97 (d,J=8.6 Hz, 2H), 4.99 (s, 2H), 4.39 (t, J=7.0 Hz, 2H), 3.88 (s, 3H),2.52-2.58 (m, 2H), 1.81 (quin, J=7.2 Hz, 2H), 1.48 (quin, J=7.6 Hz, 2H).LRMS+H⁺=477.2.

Compound 126:4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(5-fluoro-7-nitro-1H-indol-2-yl)oxazole

Step 1: ethyl 5-fluoro-7-nitro-1H-indole-2-carboxylate

A solution of NaNO₂ (2.320 g, 33.6 mmol) in water (NaNO2) (8.69 ml, 482mmol) was added dropwise over 20 minutes to 4-fluoro-2-nitroaniline (5g, 32.0 mmol) in water (aniline) (11.14 ml, 618 mmol) and HCl conc.(13.15 ml, 160 mmol. In a separate containing ethyl 2-methylacetoacetate(4.66 ml, 32.0 mmol) in EtOH (33.1 ml, 567 mmol) cooled to 0-5° C. wasadded dropwise KOH 45% wt. in water (8.23 ml, 96 mmol) followed byice-cold water (66.1 ml, 3667 mmol) and It was stirred for 10 minutes.To this solution was added the 1st solution dropwise and stirredovernight An orange suspension and big black chunks were formed. Thereaction mixture was extracted with Et2O (3×100 mL) and the combinedorganic layers were washed with water (2×100 mL) then with brine (100mL). The organic layer was dried over MgSO₄, filtered and concentratedto dryness to give crude ethyl (E)-ethyl2-(2-(4-fluoro-2-nitrophenyl)hydrazono)propanoate (7.30 g, 27.1 mmol,85% yield).

The previous compound in polyphosphoric acid (41.5 ml, 873 mmol) washeated to 110° C. for 1 hour then cooled to 75° C. After 3 hrs, themixture was cooled to 20° C. and water (100 mL) was added and stirredfor 30 minutes. EA was then added (600 mL) and the aqueous phase wasneutralized with sat. NaHCO₃(300 mL) (not close to neutral pH). Morewater was added (500 mL) and then solid NaHCO₃(ca. 250 g). More water(500 mL) and EtOAc (500 mL) were added and the mixture was filtered. Thesolid was washed solids with Water (500 mL) and EtOAc (500 mL). Thelayers were separated and the organic layer was washed with water (500mL) and with brine (300 mL). The organic layer was dried over MgSO₄,filtered and concentrated to give 3.42 g as a brown solid. The residuewas purified on ISCO using a RediSep Gold column (Hex/EtOAc). The crudeproduct was dissolved and loaded onto a pre-column (dissolved crude inEtOAc). A second purification was needed to yield ethyl5-fluoro-7-nitro-1H-indole-2-carboxylate (585 mg, 8.55% yield). ¹H NMR(DMSO-d₆) δ: 11.59 (br. s., 1H), 8.18 (dd, J=9.0, 2.3 Hz, 1H), 8.12 (dd,J=8.6, 2.3 Hz, 1H), 7.44 (s, 1H), 4.39 (q, J=7.0 Hz, 2H), 1.36 (t, J=7.0Hz, 3H).

Step 2: 5-fluoro-7-nitro-1H-indole-2-carboxylic acid

To ethyl 5-fluoro-7-nitro-1H-indole-2-carboxylate (0.585 g, 2.320 mmol)in ethanol (5.76 ml, 99 mmol) was added a solution of potassiumhydroxide (0.390 g, 6.96 mmol) in water (1.529 ml, 85 mmol). Stirred at20° C. After 1 hr at rt it was heated to 60° C. for 2 hrs. It wasconcentrated to dryness and the crude dissolved in water (30 mL) byheating to 60° C. HCl (3.02 ml, 6.03 mmol) was added and crystallizationstarted. Cooled to 20° C. and stirred for 1 hour. The solids werefiltered and the cake was washed with water (2×2.5 mL) and dried underhigh vacuum until constant weight (500 mg, 96% yield). ¹H NMR (DMSO-d₆)δ: 10.80 (br. s., 1H), 8.05-8.08 (m, J=2.3, 2.3, 2.3 Hz, 1H), 8.02-8.05(m, 1H), 7.12 (s, 1H)

Step 3: 4-(chloromethyl)-2-(5-fluoro-7-nitro-1H-indol-2-yl)oxazole

This compound was prepared in a similar fashion as compound 3A/B step 1and 2 from the previous carboxylic acid. ¹H NMR (DMSO-d₆) δ:11.95 (br.s., 1H), 8.40 (s, 1H), 8.03-8.13 (m, 2H), 7.39 (s, 1H), 4.80 (s, 2H).

Step 4:4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(5-fluoro-7-nitro-1H-indol-2-yl)oxazole

To a cooled 0° C. suspension of NaH 60% wt. (6.39 mg, 0.160 mmol) in DMF(565 μl, 7.29 mmol) was added 4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenol(26.2 mg, 0.121 mmol). It was warmed to 20° C. and stirred for 30minutes and cooled back to 0° C.4-(chloromethyl)-2-(5-fluoro-7-nitro-1H-indol-2-yl)oxazole (35 mg, 0.118mmol) was added and this was stirred at 0° C. for 1 hour and slowlywarmed to 20° C. overnight. Added more NaH 60% wt ca. until completion.After 42 hours, HPLCI. MeOH (565 μl, 13.97 mmol) was added followed bywater (565 μl, 31.4 mmol) and crystallization started. After 3 h ofstirring the solids were collected and the cake was washed withMeOH:water (1:1, 3×0.5 mL) then with Hexane (3×1 mL). The product wasdried under high vacuum until constant weight. (47 mg, 83% yield). ¹HNMR (DMSO-d₆) δ: 11.97 (br. s., 1H), 8.41 (s, 1H), 8.10-8.13 (m, 1H),8.06 (dq, J=9.0, 2.1 Hz, 2H), 7.68-7.73 (m, 1H), 7.36 (s, 1H), 7.08-7.14(d, J=8.6 Hz, 2H), 6.93-7.01 (m, 2H), 5.06 (s, 2H), 4.39 (t, J=7.0 Hz,2H), 2.54 (t, J=7.8 Hz, 2H), 1.81 (quin, J=7.3 Hz, 2H), 1.48 (quin,J=7.6 Hz, 2H). LRMS+H⁺=477.2.

Compound 127:4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(6-fluoro-1H-indol-2-yl)oxazole

Step 1: 4-(chloromethyl)-2-(6-fluoro-1H-indol-2-yl)oxazole

This compound was prepared in a similar fashion as compound 3A/B step 1and 2 from 4-(chloromethyl)-2-(6-fluoro-1H-indol-2-yl)oxazole. ¹H NMR(DMSO-d₆) δ: 12.19 (br. s., 1H), 8.27 (s, 1H), 7.65 (dd, J=8.6, 5.5 Hz,1H), 7.15 (dd, J=10.0, 2.2 Hz, 1H), 7.11 (d, J=1.6 Hz, 1H), 6.90-6.99(m, 1H), 4.77 (s, 2H).

Step 2:4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(6-fluoro-1H-indol-2-yl)oxazole

This compound was prepared in a similar fashion as compound 32 step 2from the previous chloride and the corresponding phenol. ¹H NMR(DMSO-d₆) δ: 12.18 (s, 1H), 8.30 (s, 1H), 8.11 (s, 1H), 7.70 (s, 1H),7.65 (dd, J=8.8, 5.7 Hz, 1H), 7.14 (dd, J=10.0, 2.2 Hz, 1H), 7.10 (d,J=8.2 Hz, 3H), 6.90-6.99 (m, 3H), 5.03 (s, 2H), 4.39 (t, J=7.0 Hz, 2H),2.52-2.57 (m, 2H), 1.81 (quin, J=7.3 Hz, 2H), 1.48 (quin, J=7.6 Hz, 2H).LRMS+H⁺=432.1.

Compound 128:4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(4,6-difluoro-1H-indol-2-yl)oxazole

This compound was prepared in a similar fashion as compound 127 startingwith 4,6-difluoro-1H-indole-2-carboxylic acid. ¹H NMR (DMSO-d₆) δ: 12.56(s, 1H), 8.33 (s, 1H), 8.11 (s, 1H), 7.70 (s, 1H), 7.07-7.14 (m, 3H),7.04 (dd, J=9.2, 1.8 Hz, 1H), 6.88-6.99 (m, 3H), 5.04 (s, 2H), 4.39 (t,J=7.0 Hz, 2H), 2.52-2.57 (m, 2H), 1.81 (quin, J=7.3 Hz, 2H), 1.48 (quin,J=7.6 Hz, 2H). LRMS+H⁺=450.1.

Compound 129:4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(6-nitro-1H-indol-2-yl)oxazole

This compound was prepared in a similar fashion as compound 127 startingwith 6-nitro-1H-indole-2-carboxylic acid.

¹H NMR (DMSO-d₆) δ: 12.90 (br. s., 1H), 8.42 (s, 1H), 8.31 (d, J=1.6 Hz,1H), 8.11 (s, 1H), 7.95 (dd, J=8.8, 2.2 Hz, 1H), 7.85 (d, J=9.0 Hz, 1H),7.70 (s, 1H), 7.29 (s, 1H), 7.07-7.13 (d, J=8.2 Hz, 2H), 6.93-6.99 (d,J=8.2 Hz, 2H), 5.07 (s, 2H), 4.39 (t, J=7.0 Hz, 2H), 2.52-2.57 (m, 2H),1.81 (quin, J=7.3 Hz, 2H), 1.48 (quin, J=7.5 Hz, 2H). LRMS+H⁺=459.1.

Compound 130:(E)-4-((4-((3-(1H-1,2,3-triazol-1-yl)propyl)thio)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

Step 1: 3-(1H-1,2,3-triazol-1-yl)propan-1-ol and3-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)propan-1-ol

These compounds were prepared in a similar fashion as compound 2 step 1and used as a mixture for the next step. ¹H NMR (CDCl₃) for the firstcompound δ 2.00 (br. s., 1H) 2.14 (quin, J=6.20 Hz, 2H) 3.65 (t, J=5.87Hz, 2H) 4.56 (t, J=6.65 Hz, 2H) 7.59 (s, 1H) 7.71 (s, 1H) and for thesecond compound δ ppm 0.32 (s, 9H) 2.13 (quint, J=6.20, 2H) 3.65 (t,J=5.67 Hz, 2H) 4.54 (t, J=6.65 Hz, 2H) 7.54 (s, 1H).

Step 2: 4-((3-(1H-1,2,3-triazol-1-yl)propyl)thio)phenol

A mixture of the previous alcohols was converted to the methanesulfonateaccording to a similar procedure described for compound 1 step 1 and thecrude was heated in DMF at 60° C. overnight with 4-methoxybenzenethioland potassium carbonate. It was then diluted with water-EA, separatedand the aqueous layer extracted with EA. The combined organic layerswere dried over Na₂SO₄, filtered and the solvent removed. The obtainedcrude was heated in aqueous HBr (48%) overnight and then the solvent wasremoved. The residue was diluted in EA-NaHCO₃(water) and the pH adjustedto almost neutral. The organic phase was separated, dried and thesolvent removed. Purification on ISCO using a RediSep® column (Hx/EA;20-100%) gave the title compound. LRMS+H⁺=236.1.

Step 3:(E)-4-((4-((3-(1H-1,2,3-triazol-1-yl)propyl)thio)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

FC This compound was prepared in a similar fashion as compound 32 step 2from the previous phenol and the corresponding chloride. ¹H NMR(DMSO-d₆) δ: 2.01 (quint, J=7.00, 7.00, 7.00, 7.00, 7.00, 7.00 Hz, 2H)2.80 (t, J=7.24 Hz, 2H) 4.46 (t, J=6.85 Hz, 2H) 5.02 (s, 2H) 6.98-7.03(m, 2H) 7.28-7.34 (m, 2H) 7.38 (d, J=16.82 Hz, 1H) 7.58 (d, J=16.43 Hz,1H) 7.63 (d, J=7.83 Hz, 1H) 7.68-7.71 (m, 1H) 7.76 (d, J=9.78 Hz, 1H)8.09 (d, J=0.78 Hz, 1H) 8.14 (t, J=8.02 Hz, 1H) 8.26 (s, 1H).LRMS+H⁺=504.9.

Compound 131:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)thiazole

Step 1: (E)-3-(2-fluoro-4-(trifluoromethyl)phenyl)acrylamide

This compound was prepared in a similar fashion as compound 3A/B step 1from the corresponding carboxylic acid. ¹H NMR (DMSO-d₆) δ: 6.83 (d,J=16.04 Hz, 1H) 7.31 (br. s., 1H) 7.50 (d, J=16.04 Hz, 1H) 7.64 (d,J=7.83 Hz, 1H) 7.68-7.80 (m, 2H) 7.85-7.93 (m, 1H).

Step 2: (E)-3-(2-fluoro-4-(trifluoromethyl)phenyl)prop-2-enethioamide

In a 25 mL round-bottomed flask were added(E)-3-(2-fluoro-4-(trifluoromethyl)phenyl)acrylamide (0.4 g, 1.716 mmol)in THE (7.80 ml, 95 mmol) to give a colorless solution. Lawesson'sreagent (0.416 g, 1.029 mmol) was added to the previous amide (0.4 g,1.716 mmol) in THE (7.80 ml, 95 mmol) and stirred overnight at rt. Itwas then heated to reflux for 48 h. Continued stirring for an extra 16hours at reflux then cooled to 20° C. and concentrated to dryness. Thecrude was dissolved in CH₂Cl₂ (7.78 ml, 121 mmol) and silica gel wasadded (3 g). Concentrated under reduced pressure and the residue waspurified on ISCO using a RediSep column (Hex/EtOAc; 0-100%) to give thetitle compound (245 mg, 0.983 mmol, 57.3% yield) as a yellow solid. ¹HNMR (DMSO-d₆) δ: 9.78 (br. s., 1H), 9.46 (br. s., 1H), 7.92 (t, J=7.8Hz, 1H), 7.79 (d, J=10.6 Hz, 1H), 7.74 (d, J=15.7 Hz, 1H), 7.65 (d,J=8.2 Hz, 1H), 7.18 (d, J=15.7 Hz, 1H).

Step 3:(E)-4-(chloromethyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)thiazole

A mixture of(E)-3-(2-fluoro-4-(trifluoromethyl)phenyl)prop-2-enethioamide (100 mg,0.401 mmol) and 1,3-dichloropropan-2-one (61.1 mg, 0.481 mmol) in EtOH(820 μl, 14.04 mmol) in a sealed vial was heated to reflux (ca. 85° C.)for 1 hr. The solvent was removed and the residue was purified on ISCOusing a RediSep column (Hex/EtOAc; 0-50%) to yield the title compound(69 mg, 0.214 mmol, 53.5% yield). ¹H NMR (DMSO-d₆) 5:8.13 (t, J=7.8 Hz,1H), 7.84 (s, 1H), 7.77 (d, J=11.0 Hz, 1H), 7.73 (d, J=16.4 Hz, 1H),7.64 (d, J=7.8 Hz, 1H), 7.58 (d, J=16.4 Hz, 1H), 4.87 (s, 2H).

Step 4:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)thiazole

This compound was prepared in a similar fashion as compound 32 step 2from the previous chloride the corresponding phenol. ¹H NMR (DMSO-d₆) δ:8.08-8.17 (m, 2H), 7.69-7.80 (m, 4H), 7.64 (d, J=7.8 Hz, 1H), 7.58 (d,J=16.4 Hz, 1H), 7.06-7.14 (d, J=8.6 Hz, 2H), 6.91-6.99 (d, J=8.6 Hz,2H), 5.16 (s, 2H), 4.39 (t, J=7.0 Hz, 2H), 2.52-2.57 (m, 2H), 1.81(quin, J=7.3 Hz, 2H), 1.48 (quin, J=7.6 Hz, 2H). LRMS+H⁺=503.1.

Compound 132:(E)-4-(((4-(3-(1H-1,2,3-triazol-1-yl)propyl)phenyl)thio)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

Step 1: 0-(4-(3-(1H-1,2,3-triazol-1-yl)propyl)phenyl)dimethylcarbamothioate

N Dimethylthiocarbamoyl chloride (0.365 g, 2.95 mmol) was added to4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenol (0.3 g, 1.476 mmol) in DMF(5.88 ml, 76 mmol) and this was heated to 70° C. overnight. The reactionmixture was poured into water (18 mL) and extracted with Et₂O (5×15 mL).The combined organic layers were washed with 1% wt. NaOH (10 mL) thenwith brine (10 mL). The organic layer was dried over MgSO₄, filtered andconcentrated to give a yellow oil. The residue was purified on ISCOusing a RediSep column (Hex/EtOAc; 0-100%) to give the title compound(236 mg, 0.813 mmol, 55.1% yield). ¹H NMR (DMSO-d₆) δ: 8.17 (s, 1H),7.74 (s, 1H), 7.16-7.27 (d, J=8.2 Hz, 2H), 6.93-7.02 (d, J=8.2 Hz, 2H),4.39 (t, J=7.0 Hz, 2H), 3.35 (s, 3H), 3.29 (s, 3H), 2.52-2.59 (m, 2H),2.14 (quin, J=7.4 Hz, 2H).

Step 2: S-(4-(3-(1H-1,2,3-triazol-1-yl)propyl)phenyl)dimethylcarbamothioate

A solution of 0-(4-(3-(1H-1,2,3-triazol-1-yl)propyl)phenyl)dimethylcarbamothioate (230 mg, 0.792 mmol) in diphenyl lether (1206 μl,7.58 mmol) was placed in the microwave and heated to 250° C. for 10 h.The residue was purified on ISCO using a RediSep column (Hexane). Thecrude product was dissolved and loaded onto a pre-column (medium, 10 gSiO2, dissolved crude in MeOH). Collected fractions: none. This was doneto remove PhOPh. The residue was purified on ISCO using a RediSep 12 gcolumn (Hex/EtOAc) with the drypack prepared above to give the titlecompound (129 mg, 56.1% yield). ¹H NMR (DMSO-d₆) δ: 8.17 (s, 1H), 7.74(s, 1H), 7.32-7.38 (d, J=7.8 Hz, 2H), 7.22-7.28 (d, J=7.8 Hz, 2H), 4.40(t, J=7.0 Hz, 2H), 3.03 (br. s., 3H), 2.92 (br. s., 3H), 2.55-2.62 (m,2H), 2.14 (quin, J=7.4 Hz, 2H).

Step 3: 4-(3-(1H-1,2,3-triazol-1-yl)propyl)benzenethiol

To a solution of S-(4-(3-(1H-1,2,3-triazol-1-yl)propyl)phenyl)dimethylcarbamothioate (130 mg, 0.448 mmol) in THE (578 μl, 7.05 mmol)was added a solution of KOH (60.3 mg, 1.074 mmol) in MeOH (230 μl, 5.69mmol). This was stirred overnight and the end of which the mixture waspoured in water (5 mL) and acidified with HCl (187 μl, 1.119 mmol). Theaqueous layer was extracted with EtOAc (10 mL) and the organic layerwashed with water (5 mL) and then with brine (5 mL). The organic layerwas dried over MgSO₄, filtered and concentrated to dryness. The residuewas purified on ISCO using a RediSep column (CH₂Cl₂/MeOH; 0-50%). Thecrude product was dissolved and loaded onto a pre-column (small, 4 gSiO2, dissolved crude in CH₂Cl₂) to give the title compound (56 mg,57.0% yield). ¹H NMR (DMSO-d₆) δ: 8.15 (s, 1H), 7.73 (s, 1H), 7.18-7.23(m, J=8.2 Hz, 2H), 7.05-7.12 (m, 2H), 5.28 (s, 1H), 4.36 (t, J=7.2 Hz,2H), 2.43-2.48 (m, 2H), 2.09 (quin, J=7.5 Hz, 2H). LRMS+H⁺=220.1.

Step 4:(E)-4-(((4-(3-(1H-1,2,3-triazol-1-yl)propyl)phenyl)thio)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

This compound was prepared in a similar fashion as compound 32 step 2from the previous thiol the corresponding chloride. ¹H NMR (DMSO-d₆) δ:8.09-8.18 (m, 2H), 7.97 (s, 1H), 7.77 (d, J=10.6 Hz, 1H), 7.72 (s, 1H),7.63 (d, J=8.2 Hz, 1H), 7.53 (d, J=16.4 Hz, 1H), 7.28-7.38 (m, 3H), 7.16(d, J=8.2 Hz, 2H), 4.37 (t, J=7.0 Hz, 2H), 4.12 (s, 2H), 2.52-2.56 (m,2H), 2.11 (quin, J=7.4 Hz, 2H). LRMS+H⁺=489.2.

Compound 133:(E)-4-(((6-(4-(1H-1,2,3-triazol-1-yl)butyl)pyridin-3-yl)oxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

Step 1: 4-(4-methoxyphenyl)but-3-yn-1-ol

To a degassed solution of 2-bromo-5-methoxypyridine (1.00 g, 5.3 mmol)and but-3-yn-1-ol (0.224 g, 3.19 mmol) in Et₃N (17.79 ml, 128 mmol) wasadded copper (I) iodide (0.018 g, 0.096 mmol) and PdCl₂(PPh₃)₂(0.067 g,0.096 mmol).

This was stirred overnight at 80° C. It was then filtered and thesolvent removed. The crude was purified using ISCO column (DCM-MeOH;0-15%) to give title compound (1.3 g, 81% yield). ¹H NMR (400 MHz,CDCl₃) δ 2.70 (t, J=6.26 Hz, 2H) 3.74-3.92 (m, 5H) 7.13 (dd, J=8.61,2.74 Hz, 1H) 7.34 (d, J=8.61 Hz, 1H) 8.23 (br. s., 1H).

Step 2: 4-(4-methoxyphenyl)butan-1-oI

The previous alkyne (0.41 g, 2.3 mmol) was hydrogenated with a hydrogenballoon overnight in methanol-ethyl acetate (1/1; 158 ml) with palladiumon charcoal 10%. The mixture was filtered and the solvent removed togive the title compound (0.33 g, 79%). ¹H NMR (DMSO-d₆) δ: 1.31-1.46 (m,2H) 1.57 (quin, J=7.63 Hz, 2H) 2.54 (t, J=7.63 Hz, 2H) 3.39 (q, J=6.26Hz, 2H) 4.36 (t, J=5.28 Hz, 1H) 7.16 (m, J=8.22 Hz, 2H) 7.45 (m, J=8.22Hz, 2H).

Step 3: 1-(4-(4-methoxyphenyl)butyl)-1H-1,2,3-triazole

1-(4-azidobutyl)-4-methoxybenzene was prepared in a similar fashion ascompound 1, step 2, method B from the previous alcohol and then treatedwith vinyl acetate in a similar fashion manner as compound 1 step 3 toyield the title compound. ¹H NMR (DMSO-d₆) δ: 1.55 (quint, J=7.60 Hz,2H) 1.80 (quin, J=7.34 Hz, 1H) 2.66 (t, J=7.63 Hz, 2H) 3.76 (d, J=1.57Hz, 3H) 4.37 (t, J=6.85 Hz, 2H) 7.13 (d, J=8.22 Hz, 1H) 7.27 (dd,J=8.61, 3.13 Hz, 1H) 7.68 (s, 1H) 8.09 (s, 1H) 8.15 (d, J=3.13 Hz, 1H).

Step 4: 4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenol

A mixture of 2-(4-(1H-1,2,3-triazol-1-yl)butyl)-5-methoxypyridine(0.074, 0.319 mmol) in HBr (2 ml, 17.68 mmol) was heated at 105° C.overnight and then 8 h at 120 C. Nitrogen was bubbled for 15 min then EAwas added and the mixture was quenched with solid Na₂CO₃. The layerswere separated and the aqueous layer extracted with EA. The organiclayers were combined, washed with brine, Na₂SO₄ dried, filtered and thesolvent removed to give the title compound (0.060 g, 86%). ¹H NMR(DMSO-d₆) δ: 1.55 (quint, J=7.60 Hz, 2H) 1.81 (quint, J=7.40, Hz, 2H)2.62 (t, J=7.63 Hz, 2H) 4.38 (t, J=7.04 Hz, 2H) 6.91-7.08 (m, 2H) 7.70(d, J=0.78 Hz, 1H) 8.01 (d, J=1.96 Hz, 1H) 8.10 (d, J=0.78 Hz, 1H) 9.59(s, 1H).

Step 5:(E)-4-(chloromethyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

This compound was prepared in a similar fashion as compound 3A/B step1-2 from (E)-3-(2-fluoro-4-(trifluoromethyl)phenyl)acrylic acid. ¹H NMR(DMSO-d₆) δ: 4.70 (s, 2H) 7.36 (d, J=16.43 Hz, 1H) 7.57 (d, J=16.82 Hz,1H) 7.62 (d, J=8.22 Hz, 1H) 7.75 (d, J=9.78 Hz, 1H) 8.13 (t, J=7.83 Hz,1H) 8.22 (s, 1H).

Step 6:(E)-4-(((6-(4-(1H-1,2,3-triazol-1-yl)butyl)pyridin-3-yl)oxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

This compound was prepared in a similar fashion as compound 32 step 2from the previous phenol (step 4) and the chloride of step 5. ¹H NMR(DMSO-d₆) δ: 1.58 (quin, J=7.63 Hz, 2H) 1.82 (quin, J=7.34 Hz, 2H) 2.69(t, J=7.63 Hz, 2H) 4.39 (t, J=6.85 Hz, 2H) 5.09 (s, 2H) 7.35-7.44 (m,2H) 7.60 (d, J=16.20 Hz, 1H) 7.65 (d, J=8.22 Hz, 1H) 7.70 (s, 1H) 7.79(d, J=10.96 Hz, 1H) 8.11 (s, 1H) 8.16 (t, J=7.83 Hz, 1H) 8.26 (d, J=3.13Hz, 1H) 8.30 (s, 1H). LRMS+H⁺=488.0.

Compound 134:(E)-4-(4-(4-(1H-1,2,3-triazol-1-yl)butyl)benzyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

Step 1: 4-(4-bromophenyl)butan-1-ol

BH₃·THF (6.17 ml, 6.17 mmol) was added to a 0° C. solution of4-(4-bromophenyl)butanoic acid (1.0 g, 4.11 mmol) in THE (13.71 ml) andlet go to rt overnight. It was cooled back and the same quantities ofBH₃. THF was added and let go overnight at rt. The mixture was quenchedwith HOAc (2.5 mL) and brought to rt for 30 min. It was diluted with EAand the layers separated. The aqueous was extracted with EA, the organiccombined and washed with brine. After drying over Na₂SO₄, it wasfiltered and the solvent removed to give the title compound (0.85 g,90%). ¹H NMR (DMSO-d) 5: 1.31-1.46 (m, 2H) 1.57 (quin, J=7.63 Hz, 2H)2.54 (t, J=7.63 Hz, 2H) 3.39 (q, J=6.26 Hz, 2H) 4.36 (t, J=5.28 Hz, 1H)7.16 (m, J=8.22 Hz, 2H) 7.45 (m, J=8.22 Hz, 2H).

Step 2: 1-(4-(4-bromophenyl)butyl)-1H-1,2,3-triazole

This compound was prepared in a similar fashion as for compound 133 step3. ¹H NMR (DMSO-d₆) δ: 1.42-1.56 (m, 2H) 1.74-1.85 (m, 2H) 2.57 (t,J=7.83 Hz, 2H) 4.39 (t, J=7.04 Hz, 2H) 7.09-7.16 (m, 2H) 7.40-7.48 (m,2H) 7.70 (d, J=0.78 Hz, 1H) 8.11 (d, J=0.78 Hz, 1H).

Step 3:1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyl)-1H-1,2,3-triazole

A degassed mixture of the previous bromide (1.0 eq.), potassium acetate(5.0 eq.), bis(pinacolato)diboron (1.5 eq.) and PdCl₂.dppf (0.2 eq.) washeated at 100° C. 2 h. The mixture was quenched with NH₄Cl solution anddiluted with EA. The layers were separated and the aqueous was extractedwith EA. The combined organic layers were washed with brine, Na₂SO₄dried, filtered and solvent removed. Purification on ISCO using aRediSep® column (Hx/EA; 20-100%) gave the title compound (0.072 g, 61%).¹H NMR (DMSO-d₆) δ: 1.28 (s, 12H) 1.51 (quin, J=7.53 Hz, 2H) 1.80 (quin,J=7.34 Hz, 1H) 2.61 (s, 2H) 4.39 (t, J=7.04 Hz, 2H) 7.18 (m, J=7.83 Hz,2H) 7.58 (m, J=7.43 Hz, 2H) 7.70 (s, 1H) 8.10 (s, 1H).

Step 4: Compound 134:(E)-4-(4-(4-(1H-1,2,3-triazol-1-yl)butyl)benzyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

A degassed mixture of the previous triazole (1.0 eq.), sodium carbonate(1.0 eq.), (Ph₃)P)₄Pd (0.05 eq,) and(E)-4-(chloromethyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole washeated overnight at 80° C. The mixture was quenched with NH₄Cl solutionand diluted with EA. The layers were separated and the aqueous wasextracted with EA. The combined organic layers were washed with brine,Na₂SO₄ dried, filtered and solvent removed. Purification on ISCO using aRediSep® column (Hx/EA; 5-100%) gave an impure compound. A secondpurification with toluene-EA (0-70%) was necessary to give the titlecompound (0.015 g, 14%). ¹H NMR (DMSO-d₆) δ: 1.49 (quin, J=7.63 Hz, 2H)1.81 (quin, J=7.60 Hz, 2H) 2.56 (t, J=7.63 Hz, 2H) 3.82 (s, 2H) 4.39 (t,J=7.04 Hz, 2H) 7.10 (d, J=8.22 Hz, 2H) 7.18 (d, J=7.83 Hz, 2H) 7.33 (d,J=16.43 Hz, 1H) 7.51 (d, J=16.43 Hz, 1H) 7.62 (d, J=8.22 Hz, 1H) 7.70(s, 1H) 7.76 (d, J=9.78 Hz, 1H) 7.92 (s, 1H) 8.07-8.19 (m, 2H).LRMS+H⁺=471.1.

Compound 135:(E)-4-((4-(4-(4H-1,2,4-triazol-4-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazoleand Compound 136:(E)-N-(4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)formamide

Step 1:(E)-4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butan-1-amine

To(E)-4-((4-(4-azidobutyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole(0.200 g, 0.43 mmol) in THE (0.29 ml) was added Ph₃P (0.171 g, 0.65mmol) and water (0.012 ml, 0.65 mmol). The mixture was stirred 18 h andthe solvent was removed. Purification on ISCO using a RediSep® column(DCM-MeOH—NH₄OH; 77.5-22-2.5%; 0-70%) gave 0.168 g of the amine product.

Step 2:(E)-N-(4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)formamide

Triethyl orthoformate (0.055 ml, 0.33 mmol) and formohydrazide (0.013 g,0.22 mmol) in MeOH (0.12 ml) was heated to 70° C. for 2.5 h. Then theprevious amine (0.080 g, 0.184 mmol) was added and the mixture heatedovernight. It was absorbed on SiO₂ and purified on ISCO using a RediSep®column (Hex/EtOAc; 0-100%) followed by MeOH (7%) in EA to give 12 mg ofcompound 135; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32-1.45 (m, 2H)1.47-1.58 (m, 2H) 3.09 (q, J=6.65 Hz, 2H) 5.00 (s, 2H) 6.91-6.98 (m, 2H)7.12 (m, J=8.61 Hz, 2H) 7.39 (d, J=16.43 Hz, 1H) 7.59 (d, J=16.82 Hz,1H) 7.65 (d, J=8.22 Hz, 1H) 7.78 (d, J=9.78 Hz, 1H) 7.93-8.05 (m, 2H)8.16 (t, J=7.83 Hz, 1H) 8.27 (s, 1H) and 54 μmg of compound 136(E)-N-(4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)formamide¹H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.45 (m, 2H) 1.47-1.58 (m, 2H) 3.09(q, J=6.65 Hz, 2H) 5.00 (s, 2H) 6.91-6.98 (m, 2H) 7.12 (d, J=8.61 Hz,2H) 7.39 (d, J=16.43 Hz, 1H) 7.59 (d, J=16.82 Hz, 1H) 7.65 (d, J=8.22Hz, 1H) 7.78 (d, J=9.78 Hz, 1H) 7.93-8.05 (m, 2H) 8.16 (t, J=7.83 Hz,1H) 8.27 (s, 1H).

Compound 137:(E)-4-(4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butyl)thiomorpholine1,1-dioxide

(vinylsulfonyl)ethene (5.7 μl, 0.058 mmol) in toluene (2.5 ml) was addedportionwise to a 80° C. solution of(E)-4-(4-((2-(2-fluoro-4-(trifluoromethyl)styryl)oxazol-4-yl)methoxy)phenyl)butan-1-amine(0.025 g, 0.058 mmol) in i-propanol (5.7 ml). After 5 h of heating thesolvent was removed and the crude purified on ISCO using a RediSep®column Hex/EtOAc; 0-100%) to give 22 mg of the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.33-1.46 (m, 2H) 1.48-1.59 (m, 2H) 2.45 (t,J=7.24 Hz, 2H) 2.51-2.56 (m, 2H) 2.83 (br. s., 4H) 3.04 (d, J=5.09 Hz,4H) 5.00 (s, 2H) 6.94 (d, J=8.61 Hz, 2H) 7.12 (d, J=8.61 Hz, 2H) 7.39(d, J=16.43 Hz, 1H) 7.59 (d, J=16.43 Hz, 1H) 7.66 (s, 1H) 8.16 (t,J=7.83 Hz, 1H) 8.27 (s, 1H).

Compound 138:(E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(pyridazin-3-yl)butyl)phenoxy)methyl)oxazole

Step 1: 3-(4-(4-(benzyloxy)phenyl)but-1-yn-1-yl)pyridazine

A degassed mixture of 1-(benzyloxy)-4-(but-3-yn-1-yl)benzene (0.250 g;1.06 mmol), 3-bromopyridazine (0.185 g; 1.16 mmol), copper iodode (0.008g; 0.042 mmol) and PdCl₂(Ph₃P)₂ (0.030 g, 0.042 mmol) in triethylamine(5.3 ml) was heated overnight at 85° C. It was then diluted withwater-EA and the organic phase separated. The aqueous phase wasextracted twice with EA and then were combined, fried and the solventremoved. Purification on ISCO using a RediSep® column Hex/EtOAc; 0-100%)to give 163 mg of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.72-2.79 (m, 2H) 2.80-2.87 (m, 2H) 5.05 (s, 2H) 6.84-6.98 (m, 2H) 7.23(d, J=8.61 Hz, 2H) 7.31 (s, 1H) 7.36 (t, J=7.24 Hz, 2H) 7.39-7.44 (m,2H) 7.58-7.71 (m, 2H) 9.14 (dd, J=4.11, 2.54 Hz, 1H).

Step 2: 3-(4-(4-(benzyloxy)phenyl)butyl)pyridazine

The previous alkyne was hydrogenated according to step 2 of compound 99in MeOH. LRMS+H⁺: 319.1.

Step 3: 4-(4-(pyridazin-3-yl)butyl)phenol

Debenzylation was done according to step 4 compound 107. ¹H NMR (400MHz, CDCl₃) δ ppm 1.62-1.72 (m, 2H) 1.83 (quin, J=7.63 Hz, 2H) 2.58 (t,J=7.63 Hz, 2H) 3.05 (t, J=7.43 Hz, 2H) 5.41 (br. s., 1H) 6.65-6.77 (m,2H) 7.01 (d, J=8.61 Hz, 2H) 7.18 (d, J=3.13 Hz, 1H) 7.67 (d, J=3.52 Hz,1H).

Step 4:(E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(pyridazin-3-yl)butyl)phenoxy)methyl)oxazole

This compound was prepared from the previous phenol according to step 3of compound 88. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.56 (quin, J=7.34 Hz,2H) 1.69 (quin, J=7.40 Hz, 2H) 2.54 (t, J=7.43 Hz, 2H) 2.90 (t, J=7.63Hz, 2H) 4.97 (s, 2H) 6.92 (d, J=8.61 Hz, 2H) 7.09 (d, J=8.61 Hz, 2H)7.37 (d, J=16.60 Hz, 1H) 7.51-7.65 (m, 4H) 7.76 (d, J=10.17 Hz, 1H) 8.14(t, J=7.63 Hz, 1H) 8.24 (s, 1H) 9.04 (dd, J=4.70, 1.96 Hz, 1H).

Compound 139:(E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(pyrimidin-2-yl)butyl)phenoxy)methyl)oxazole

Step 1: 2-(4-(4-(benzyloxy)phenyl)but-1-yn-1-yl)pyrimidine

This compound was prepared in a similar fashion as compound 108 step 1with 2-iodopyrimidine.

LRMS+H⁺: 315.1.

Step 2: 4-(4-(pyrimidin-2-yl)butyl)phenol

This compound was prepared by hydrogenation with Pd/C in MeOH-EA at 1atmosphere in methanol. LRMS+H⁺: 229.1.

Step 3:(E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(pyrimidin-2-yl)butyl)phenoxy)methyl)oxazole

This compound was prepared with the previous phenol and(E)-4-(chloromethyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole in asimilar fashion as compound 26, step 3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.55 (quin, J=7.50 Hz, 2H) 1.72 (quin, J=7.53 Hz, 2H) 2.53 (t, J=7.63Hz, 2H) 2.85 (t, J=7.43 Hz, 2H) 4.97 (s, 2H) 6.92 (d, J=8.61 Hz, 2H)7.08 (d, J=8.61 Hz, 2H) 7.29 (t, J=4.89 Hz, 1H) 7.37 (d, J=16.43 Hz, 1H)7.57 (d, J=16.43 Hz, 1H) 7.62 (d, J=8.22 Hz, 1H) 7.76 (d, J=10.56 Hz,1H) 8.14 (t, J=7.83 Hz, 1H) 8.24 (s, 1H) 8.68 (d, J=4.70 Hz, 2H).LRMS+H⁺=498.0.

Compound 140:(E)-2-(2-fluoro-4-(trifluoromethyl)styryl)-4-((4-(4-(pyridin-2-yl)butyl)phenoxy)methyl)oxazole

This compound was prepaed in a similar fashion as compound 138 startingwith 2-bromopyridine. ¹H NMR (400 MHz, DMSO-d₆) δ 1.47-1.59 (m, 2H)1.59-1.70 (m, 2H) 2.52 (t, J=7.40 Hz, 2H) 2.71 (t, J=7.43 Hz, 2H) 4.97(s, 2H) 6.91 (d, J=8.22 Hz, 2H) 7.08 (d, J=8.22 Hz, 2H) 7.15 (dd,J=6.65, 5.09 Hz, 1H) 7.20 (d, J=7.83 Hz, 1H) 7.37 (d, J=16.43 Hz, 1H)7.57 (d, J=16.43 Hz, 1H) 7.60-7.68 (m, 2H) 7.77 (d, J=10.17 Hz, 1H) 8.14(t, J=7.83 Hz, 1H) 8.24 (s, 1H) 8.43 (d, J=4.70 Hz, 1H). LRMS+H⁺=497.0.

Compound 141:(E)-4-(2-(4-((4-((3-(1H-1,2,3-triazol-1-yl)propyl)thio)phenoxy)methyl)oxazol-2-yl)vinyl)-3-fluorobenzonitrile

This compound was prepared from(E)-4-(2-(4-(chloromethyl)oxazol-2-yl)vinyl)-3-fluorobenzonitrile and4-((3-(1H-1,2,3-triazol-1-yl)propyl)thio)phenol according to compound130, step 3. ¹H NMR (400 MHz, DMSO-d₆) δ 8.29 (s, 1H), 8.09-8.17 (m,2H), 7.95 (d, J=10.6 Hz, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.71 (s, 1H), 7.57(d, J=16.4 Hz, 1H), 7.43 (d, J=16.4 Hz, 1H), 7.30-7.36 (d, J=8.6 Hz,2H), 6.99-7.06 (d, J=8.6 Hz, 2H), 5.03 (s, 2H), 4.48 (t, J=6.8 Hz, 2H),2.82 (t, J=7.0 Hz, 2H), 2.03 (quin, J=7.0 Hz, 2H). LRMS+H⁺=462.1.

Compound 142:4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(6-fluorobenzofuran-2-yl)oxazole

Step 1: 6-fluorobenzofuran-2-carboxamide

This compound was prepared from hydrolysis (KOH) of ethyl6-fluorobenzofuran-2-carboxylate followed the procedure used to preparedcompound 3, step 1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (br. s., 1H), 7.80(dd, J=8.8, 5.7 Hz, 1H), 7.67 (br. s., 1H), 7.58 (dd, J=9.4, 2.0 Hz,1H), 7.55 (d, J=0.8 Hz, 1H), 7.23 (ddd, J=9.8, 8.8, 2.2 Hz, 1H).

Step 2: 4-(chloromethyl)-2-(6-fluorobenzofuran-2-yl)oxazole

This compound was prepared from the previous intermediate in a similarfashion as compound 58, step 3. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (s,1H), 7.81 (dd, J=8.8, 5.7 Hz, 1H), 7.72 (dd, J=9.4, 2.0 Hz, 1H), 7.69(s, 1H), 7.22-7.31 (m, 1H), 4.77 (s, 2H).

Step 3:4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(6-fluorobenzofuran-2-Ioxazole

This compound was prepared in a similar fashion as compound 113, step 3with the previous intermediate and4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenol. ¹H NMR (400 MHz, DMSO-d₆) δ8.39 (s, 1H), 8.11 (s, 1H), 7.80 (dd, J=8.6, 5.5 Hz, 1H), 7.65-7.75 (m,3H), 7.26 (td, J=9.3, 2.2 Hz, 1H), 7.07-7.13 (d, J=8.2 Hz, 2H),6.93-6.99 (d, J=8.6 Hz, 2H), 5.04 (s, 2H), 4.39 (t, J=7.0 Hz, 2H),2.52-2.58 (m, 2H), 1.81 (quin, J=7.3 Hz, 2H), 1.48 (quin, J=7.6 Hz, 2H).

Compound 143:4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(6-fluorobenzo[b]thiophen-2-yl)oxazole

This compound was prepared in a similar fashion as compound 140 startingwith ethyl 6-fluorobenzo[b]thiophene-2-carboxylate. ¹H NMR (400 MHz,DMSO-d₆) δ 8.34 (s, 1H), 8.10 (d, J=7.0 Hz, 2H), 7.97-8.05 (m, 2H), 7.70(s, 1H), 7.36 (td, J=9.1, 2.2 Hz, 1H), 7.07-7.14 (d, J=8.6 Hz, 2H),6.93-7.00 (d, J=8.6 Hz, 2H), 5.02 (s, 2H), 4.39 (t, J=6.8 Hz, 2H),2.52-2.57 (m, 2H), 1.81 (quin, J=7.3 Hz, 2H), 1.48 (quin, J=7.6 Hz, 2H).LRMS+H⁺=449.1.

Compound 144:4-((4-((3-(1H-1,2,3-triazol-1-yl)propyl)thio)phenoxy)methyl)-2-(4,6-difluoro-1H-indol-2-yl)oxazole

This compound was prepared in a similar fashion as compound 128 with4-(chloromethyl)-2-(4,6-difluoro-1H-indol-2-yl)oxazole and4-((3-(1H-1,2,3-triazol-1-yl)propyl)thio)phenol. ¹H NMR (400 MHz,DMSO-d₆) δ 12.56 (br. s., 1H), 8.35 (s, 1H), 8.11 (s, 1H), 7.71 (s, 1H),7.34 (d, J=8.6 Hz, 2H), 7.12 (s, 1H), 7.04 (d, J=8.6 Hz, 3H), 6.93 (td,J=10.4, 2.0 Hz, 1H), 5.08 (s, 2H), 4.48 (t, J=7.0 Hz, 2H), 2.82 (t,J=7.2 Hz, 2H), 2.04 (quin, J=7.0 Hz, 2H). LRMS+H⁺=468.1.

Compound 145:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)-5-methyloxazole

Step 1: (E)-ethyl2-(3-(2-fluoro-4-(trifluoromethyl)phenyl)acrylamido)-3-oxobutanoate

Trietylamine (1.34 ml, 9.2 mmol) was added to a solution of(E)-3-(2-fluoro-4-(trifluoromethyl)phenyl)acryloyl chloride (1.08 g,4.28 mmol) and ethyl 2-amino-3-oxobutanoate hydrochloride (0.971 g, 5.34mmol) in dichloromethane (25.03 ml, 389 mmol) at 0° C. After 30 minutes,the mixture was poured into water (15 mL) and stirred vigorously. Thelayers were separated and the organic layer was dried over MgSO₄,filtered and concentrated. The residue was purified on ISCO using aRediSep 80 g column (Hex/EtOAc; 0-100%) to yield the title product (145mg). LRMS+H⁺=362.1.

Step 2: (E)-ethyl2-(2-fluoro-4-(trifluoromethyl)styryl)-5-methyloxazole-4-carboxylate

(E)-ethyl2-(3-(2-fluoro-4-(trifluoromethyl)phenyl)acrylamido)-3-oxobutanoate(0.145 g, 0.40 mmol) in phosphorus oxychloride (2.00 ml, 21.47 mmol) washeated to 105° C. for 2 hr. The mixture was concentrated, neutralizedwith sat. NaHCO₃ (10 mL) and extracted with CH₂Cl₂ (10 mL). The aqueouslayer was extracted with CH₂Cl₂ (5 mL) and the combined organic layerswere washed with water (5 mL). The organic layer was dried over MgSO₄,filtered and concentrated. to give a dark orange oil. The residue waspurified on ISCO using a RediSep 24 g column (Hex/EtOAc; 0-60%) to give80 mg of the title compound. ¹H NMR (DMSO-d₆) δ: 8.15 (t, J=7.8 Hz, 1H),7.79 (d, J=11.0 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.57 (d, J=16.4 Hz,1H), 7.37 (d, J=16.8 Hz, 1H), 4.29 (q, J=7.2 Hz, 2H), 2.65 (s, 3H), 1.31(t, J=7.0 Hz, 3H).

Step 3:(E)-(2-(2-fluoro-4-(trifluoromethyl)styryl)-5-methyloxazol-4-yl)methanol

To LiAlH₄ (0.011 g, 0.303 mmol) in Et₂O (1.50 ml, 14.43 mmol) at 0° C.was added a solution of (E)-ethyl2-(2-fluoro-4-(trifluoromethyl)styryl)-5-methyloxazole-4-carboxylate(0.080 g, 0.233 mmol) in THE (0.50 ml, 6.11 mmol) and Et₂O (1.000 ml,9.62 mmol). After 30 minutes, it was warmed to 20° C. and stirred for 15minutes. Some MgSO₄ was added and the mixture filtered. The filtrate wasconcentrated to dryness to yield the title compound (53 mg, 75% yield).LRMS+H⁺=302.1.

Step 4:(E)-4-(chloromethyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)-5-methyloxazole

Thionyl chloride (0.064 ml, 0.88 mmol) was added dropwise to a solutionof(E)-(2-(2-fluoro-4-(trifluoromethyl)styryl)-5-methyloxazol-4-yl)methanol(0.053 g, 0.176 mmol) in dichloromethane (2.50 ml, 38.8 mmol) at 0° C.After 15 minutes it was then warmed to 20° C. for 45 minutes. Afterremoval of the solvent the residue was purified on ISCO using a RediSep12 g column (Hex/EtOAc; 0-30%) to yield the title compound (37 mg, 65.8%yield). 1H NMR (DMSO-d₆) δ: 8.14 (t, J=7.6 Hz, 1H), 7.77 (d, J=11.0 Hz,1H), 7.64 (d, J=8.2 Hz, 1H), 7.51 (d, J=16.8 Hz, 1H), 7.32 (d, J=16.4Hz, 1H), 4.73 (s, 2H), 2.43 (s, 3H).

Step 5:(E)-4-((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)-5-methyloxazole

This compound was prepared in a similar fashion as compound 88, step 3with the previous chloride. ¹H NMR (DMSO-d₆) 5: 8.14 (t, J=8.0 Hz, 1H),8.08-8.12 (m, 1H), 7.77 (d, J=10.2 Hz, 1H), 7.70 (s, 1H), 7.63 (d, J=7.8Hz, 1H), 7.50 (d, J=16.4 Hz, 1H), 7.33 (d, J=16.4 Hz, 1H), 7.06-7.13 (d,J=8.6 Hz, 2H), 6.89-6.96 (d, J=8.6 Hz, 2H), 4.94 (s, 2H), 4.39 (t, J=7.0Hz, 2H), 2.52-2.57 (m, 2H), 2.42 (s, 3H), 1.81 (quin, J=7.2 Hz, 2H),1.48 (quin, J=7.6 Hz, 2H).

LRMS+H⁺=501.2.

Compound 146:(E)-4-(((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenyl)thio)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

Step 1: 0-(4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenyl)dimethylcarbamothioate

This compound was prepared in a similar fashion as compound 132, step 1with 4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenol. ¹H NMR (DMSO-d6) δ: 8.12(s, 1H), 7.68-7.73 (m, 1H), 7.13-7.21 (m, 2H), 6.91-6.97 (m, 2H), 4.41(t, J=7.0 Hz, 2H), 3.35 (s, 3H), 3.29 (s, 3H), 2.60 (t, J=7.8 Hz, 2H),1.83 (quin, J=7.3 Hz, 2H), 1.47-1.58 (m, 2H).

Step 2: S-(4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenyl)dimethylcarbamothioate

This compound was prepared in a similar fashion as compound 132, step 2from the previous intermediate. ¹H NMR (DMSO-d₆) δ: 8.09-8.13 (m, 1H),7.70 (d, J=0.8 Hz, 1H), 7.29-7.35 (d, 2H), 7.18-7.24 (d, J=8.2 Hz, 2H),4.40 (t, J=7.0 Hz, 2H), 2.85-3.09 (m, 6H), 2.62 (t, J=7.6 Hz, 2H), 1.83(quin, J=7.3 Hz, 2H), 1.45-1.58 (m, 2H).

Step 3: 4-(4-(1H-1,2,3-triazol-1-yl)butyl)benzenethiol

This compound was prepared in a similar fashion as compound 132, step 3from the previous intermediate. ¹H NMR (DMSO-d₆) δ: 8.10 (s, 1H), 7.70(s, 1H), 7.14-7.22 (d, J=7.8 Hz, 2H), 7.00-7.09 (d, J=8.2 Hz, 2H), 5.23(s, 1H), 4.38 (t, J=7.0 Hz, 2H), 2.52-2.56 (m, 2H), 1.79 (quin, J=7.3Hz, 2H), 1.47 (quin, J=7.6 Hz, 2H).

Step 4:(E)-4-(((4-(4-(1H-1,2,3-triazol-1-yl)butyl)phenyl)thio)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

This compound was prepared in a similar fashion as compound 132, step 4from the previous intermediate. ¹H NMR (DMSO-d₆) δ: 8.14 (t, J=7.8 Hz,1H), 8.10 (s, 1H), 7.96 (s, 1H), 7.77 (d, J=11.0 Hz, 1H), 7.70 (s, 1H),7.64 (d, J=8.2 Hz, 1H), 7.53 (d, J=16.8 Hz, 1H), 7.34 (d, J=16.8 Hz,1H), 7.25-7.31 (d, J=8.2 Hz, 2H), 7.08-7.16 (d, J=8.2 Hz, 2H), 4.39 (t,J=7.0 Hz, 2H), 4.11 (s, 2H), 2.56 (t, J=7.6 Hz, 2H), 1.81 (quin, J=7.3Hz, 2H), 1.48 (quin, J=7.6 Hz, 2H). LRMS+H⁺=503.2.

Compound 147:(E)-4-((4-((2-(1H-1,2,3-triazol-1-yl)ethyl)thio)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

Step 1: (2-azidoethyl)(4-methoxyphenyl)sulfane

2-((4-methoxyphenyl)thio)ethanol was treated with methanesulfonylchloride and trietylamine in dichlorometane as described in to yield thecrude mesylate which was in turned converted to the corresponding azidein a similar fashion as compound 109, step 2 at 70° C. The crude istaken for the net step. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.04 (t, J=6.46Hz, 2H) 3.40 (t, J=6.65 Hz, 2H) 3.73 (s, 3H) 6.84-6.96 (m, 2H) 7.25-7.41(m, 2H).

Step 2: 1-(2-((4-methoxyphenyl)thio)ethyl)-1H-1,2,3-triazole

This compound was prepared in a similar fashion as compound 1, step 3.The crude was used for the next step. ¹H NMR (400 MHz, DMSO-d₆) δ ppm3.32 (t, J=7.00 Hz, 1H) 3.74 (s, 3H) 4.47 (t, J=6.85 Hz, 1H) 6.80-6.97(m, 2H) 7.29-7.41 (m, 2H) 7.69 (d, J=1.17 Hz, 1H) 8.12 (d, J=0.78 Hz,1H).

Step 3: 4-((2-(1H-1,2,3-triazol-1-yl)ethyl)thio)phenol

This compound was prepared in a similar fashion as compound 15, step 2.The crude was used for the next step. LRMS-H⁺=220.0.

Step 4:(E)-4-((4-((2-(1H-1,2,3-triazol-1-yl)ethyl)thio)phenoxy)methyl)-2-(2-fluoro-4-(trifluoromethyl)styryl)oxazole

This compound was prepared in a similar fashion as compound 32, step 2.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.34 (t, J=6.85 Hz, 2H) 4.49 (t, J=6.85Hz, 2H) 5.03 (s, 2H) 6.96-7.07 (m, 2H) 7.33-7.44 (m, 3H) 7.58 (d,J=16.43 Hz, 1H) 7.63 (d, J=7.83 Hz, 1H) 7.69 (d, J=1.17 Hz, 1H) 7.76 (d,J=9.78 Hz, 1H) 8.10-8.18 (m, 2H) 8.28 (s, 1H).

Example 7: Biological Activity of the Heterocyclic Compounds of Example6

The potency of the compounds of Example 6 at inhibiting OCI-AML3 cellgrowth was tested using a procedure similar to that described forMutritinib in Example 1. Briefly, OCI-AML3 cells purchased from theGerman cell bank (DSMZ, accession Nos. ACC 582) were maintained inalpha-MEM, 20% FBS. Murine MLL-AF9 leukemia cells (female cells) weregenerated by infection with VSV-G-pseudotyped MSCV MLL-AF9 IRES Puro(subcloned from a construct by Frédéric Barabé, Laval U, Québec, QC,Canada).

OCI-AML3 cells were seeded in 384-well plates at a density of 150 cellsin 50 μL per well and MLL-AF9 cells at 90 cells per well. Compounds wereadded to seeded cells in serial dilutions from 10 μM to 0.5 nM, induplicates or quadruplicates. Cells treated with 0.1% DMSO withoutadditional compound were used as negative controls. Viable cell countsper well were evaluated after 6 days of culture for OCI-AML3 and 5 daysfor MLL-AF9 cells using the CellTiterGlo® assay (Promega®) according tothe manufacturer's instruction. The percent of inhibition was calculatedas follows: 100-(100×(mean luminescence(compound)/meanluminescence(DMSO)); where mean-luminescence(compound) corresponds tothe average of luminescent signals obtained for the compound-treatedcells, and mean-luminescence(DMSO) corresponds to the average ofluminescent signals obtained for the control DMSO-treated cells. EC₅₀values (corresponding to the concentration of compound required to reach50% of inhibition) were calculated using ActivityBase® SARview Suite(IDBS, London, UK) and GraphPad® Prism 4.03 (La Jolla, CA, USA) byfour-parameter-non-linear curve fitting methods. The results aresummarized in Table 4 below.

TABLE 4 Potency of the heterocyclic compounds tested at inducingOCI-AML3 and MLL-AF9 cell death AML-3 MLL-AF9 Compound EC50 EC50 1 +++++++ 2 +++ +++ 3A +++++ +++++ 3B ++ +++ 4 + ++ 5 + +++ 6 + + 7 + ++ 8 +++++ 9 + ++ 10 +++ +++++ 11 + + 12 ++ +++ 13 + + 14 + ++ 15 ++ +++ 16 ++++ 17 +++ ++++ 18 + ++ 19 +++ +++ 20 ++ +++ 21 +++ ++++ 22 ++ +++ 23+++ ++++ 24 + ++ 25 + ++ 26 + +++ 27 ++ ++++ 28 + +++ 29 + +++ 30 ++ +++31 + ++ 32 +++ +++ 33 +++ +++ 34 + + 35 + ++ 36 + + 37 +++ +++ 38 +++++++ 39 +++ +++ 40 ++++ +++ 41 +++ +++ 42 ++ +++ 43 + + 44 + − 45 +++++++ 46 ++ + 47 +++ +++ 48 ++++ +++++ 49 + + 50 + +++ 51 + ++ 52 + + 53+++ ++++ 54 +++ +++ 55 ++ +++ 56 + + 57 + ++ 58 ++ + 59 ++ +++ 60 + + 61+++ +++ 62 +++ +++ 63 ++ + 64 + ++ 65 ++++ +++++ 66 + + 67 +++ +++ 68 +++++ 69 ++ +++ 70 ++ +++ 71 +++ +++++ 72 + ++ 73 +++ +++++ 74 + +++75 + + 76 + + 77 + − 78 + − 79 + + 80 ++ +++ 81 ++++ ++++ 82 +++ +++ 83++ +++ 84 + + 85 + + 86 + +++ 87 ++ +++ 88 + ++ 89 + + 90 + +++ 91 + ++92 ++ +++ 93 + ++ 94 + + 95 + +++ 96 ++ +++ 97 +++ +++ 98 +++ ++++ 99+++ +++ 100 ++ ++ 101 + + 102 +++ +++ 103 +++ +++ 104 + + 105 +++ ++106 + + 107 + + 108 + + 109 ++ +++ 110 + + 111 + ++ 112 +++ ++++ 113 +++++ 114 + + 115 ++ +++ 116 ++++ ++++ 117 +++ +++ 118 +++ +++ 119 +++ +++120 +++ +++++ 121 ++++ ++++ 122 +++++ +++++ 123 +++ +++ 124 +++++ ++++125 ++++ +++ 126 + − 127 +++++ +++++ 128 +++++ +++++ 129 +++++ +++++ 130+++++ +++++ 131 +++ +++ 132 + ++ 133 +++ ++++ 134 + ++ 135 NT ++ 136 NT+++ 137 NT ++ 138 +++++ ++++ 139 − + 140 − + 141 +++++ ++++ 142 ++ +++143 + +++ 144 +++++ +++++ 145 ++ +++ 146 + +++ 147 +++++ +++++Activities presented as using the symbol “−” for EC₅₀ > 10 μM; + for 1μM < EC₅₀ ≤ 10 μM; ++ for 0.5 μM < EC₅₀ ≤ 1 μM; +++ for 0.1 μM < EC₅₀ ≤0.5 μM; ++++ for 0.05 μM < EC₅₀ ≤ 0.1 μM; +++++ for EC₅₀ ≤ 0.05 μM; NTfor not tested.

Numerous modifications could be made to any of the embodiments describedabove without departing from the scope of the present invention. Anyreferences, patents or scientific literature documents referred to inthe present document are incorporated herein by reference in theirentirety for all purposes.

1. A method for treating acute myeloid leukemia (AML), said methodcomprising administering to a subject in need thereof an effectiveamount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: X¹ represents—N═, —CH═, or —O—; X² represents —CH═, —C(R²)═, or a covalent bond; X³represents —CH═, —C(R²)═, or a covalent bond; X⁴ represents —O—,—C(R³)═, —N═, or —S—; and X⁵ represents a covalent bond, —C(R³)═, or—O—; provided that one of X² and X³ is —C(R²)═ and the other of X² andX³ is —CH═ or a covalent bond, and provided that at most only one of X²,X³, and X⁵ represents a covalent bond; R² represents ArylC(R³)═C(H)—,HeteroarylC(R³)═C(H)—, ArylN(R³)C(O)—, HeteroarylN(R³)C(O)—,Arylcyclopropyl-, Heteroarylcyclopropyl-, R³OC(O)C(H)═C(H)—, R³OC(O)—,Aryl-C≡C—, Heteroaryl-C═C—, Aryl-, Heteroaryl-, Aryl-CH(R³)—CH(R³)—, orHeteroaryl-CH(R³)—CH(R³)—, wherein the Aryl group and the Heteroarylgroup are optionally substituted with one to three R⁴ groups, which arethe same or different; R³ independently in each occurrence represents—H, —C₁-C₅alkyl, —C₂-C₅alkenyl, —C₂-C₅alkynyl, —C₁-C₄fluoroalkyl, or—C₃-C₇cycloalkyl, the alkyl, alkenyl, alkynyl, and cycloalkyl beingoptionally substituted with —OR⁶, —N(R⁶)₂, —C(O)OR⁶, —CN or —C(O)N(R⁶)₂;R⁴ independently in each occurrence represents —F, —Cl, —Br, —I, —SR³,—SOR⁵, —S(O)₂R⁵, —S(O)₂N(R³)₂, -triazolyl, —CN, —C(O)OR³, —C(O)R³, —NO₂,—C(O)N(R³)₂, —OR³, —C(R³)₂OH, —N(R³)₂, —N(R³)C(O)R³, —N(R³)C(O)OR⁵,—OC(O)N(R³)₂, —N₃, —R³,

R⁵ independently in each occurrence represents —C₁-C₅alkyl,—C₂-C₅alkenyl, —C₂-C₅alkynyl, —C₁-C₄fluoroalkyl, or —C₃-C₇cycloalkyl,the alkyl, alkenyl, alkynyl, and cycloalkyl being optionally substitutedwith —OR⁶, —N(R⁶)₂, —C(O)OR⁶, —CN or —C(O)N(R⁶)₂; R⁶ independentlyrepresents —H, —C₁-C₅alkyl, —C₂-C₅alkenyl, —C₂-C₅alkynyl,—C₁-C₄fluoroalkyl, or —C₃-C₇cycloalkyl; L¹ represents —CHR³—O—,—CH₂—NH—, —C(O)NH—, —C(O)—CHR⁶, —CR⁶═CR⁶—, —CH₂—S—, —CH₂, or—CH₂—O—CH₂—; X⁶ and X⁷ independently represent —CR³═, or —N═; L²represents a covalent bond, —C(O)—, —C(R³)(OH)—, —O—, —S—, —CHR³—,—CH(R³)—S—, or —CH(R³)—O—; m independently in each occurrence representsan integer from 1 to 4; p represents an integer from 1 to 6; and R¹represents heteroaryl, aryl, —N₃, —OH, —OC(O)N(R⁷)₂, —C(O)N(R⁷)₂,—N(R⁷)₂, —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁸, —N(R⁷)C(O)-L³—OR⁷, or—N(R⁷)C(O)-L³—OC(O)N(R⁷)₂, the heteroaryl and aryl being optionallysubstituted with one or more R⁹, which are the same or different,wherein: L³ represents C₁-C₅alkylene, C₂-C₅alkenylene, C₂-C₅alkynylene,or C₁-C₄fluoroalkylene, the alkylene, alkenylene, and alkynylene beingoptionally substituted with one or more R⁹, which are the same ordifferent; R⁷ independently represents —H, —C₁-C₅alkyl, —C₂-C₅alkenyl,—C₂-C₅alkynyl, —C₁-C₄fluoroalkyl, or —C₃-C₇cycloalkyl; the alkyl,alkenyl, alkynyl, and cycloalkyl being optionally substituted with oneor more R⁹, which are the same or different, or when two R⁷ groups areattached to a same nitrogen atom, the two R⁷ groups together with thenitrogen atom to which they are attached optionally form a 5-7-memberedheterocycloalkyl, the heterocycloalkyl optionally comprising one or morefurther heteroatom independently selected from —O—, —N(R³)—, —S—, —S(O)—and —SO₂—, the heterocycloalkyl being optionally substituted with one ormore R⁹, which are the same or different; R⁸ independently represents—C₁-C₅alkyl, —C₂-C₅alkenyl, —C₂-C₅alkynyl, —C₁-C₄fluoroalkyl, or—C₃-C₇cycloalkyl; the alkyl, alkenyl, alkynyl, and cycloalkyl beingoptionally substituted with one or more R⁹, which are the same ordifferent; and R⁹ independently represents —C₁-C₆alkyl,—C₀-C₆alkyl-OR¹¹, —C₃-C₆cycloalkyl, —C₃-C₆cycloalkyl-OR¹¹,—C₁-C₆alkyl-OC(O)R¹¹, —C₁-C₆alkyl-OC(O)N(R¹¹)₂,—C₁-C₆alkyl-OC(O)N(R¹¹)-L⁴—OR¹¹, —C₀-C₆alkyl-C(O)OR¹¹,—C₀-C₆alkyl-C(O)N(R¹¹)₂, —C₁-C₆alkyl-N(R¹¹)₂, —C₁-C₆alkyl-N(R¹¹)C(O)R¹¹,—C₁-C₆alkyl-N(R¹¹)C(O)-L⁴-N(R¹¹)—C(O)R¹¹, —C₁-C₆alkyl-N(R¹¹)S(O)₂R¹⁰,—C₁-C₆alkyl-N(R¹¹)S(O)₂-L⁴-N(R¹¹)—C(O)OR¹⁰, —Si(C₁-C₅alkyl)₃, —C(O)—0-C₁-C₆alkyl, phenyl optionally substituted with R⁴, benzyl optionallysubstituted with R⁴, pyridinyl optionally substituted with R⁴, or

wherein: L⁴ represents C₁-C₅alkylene, C₂-C₅alkenylene, C₂-C₅alkynylene,or C₁-C₄fluoroalkylene; and R¹⁰ independently represents —C₁-C₅alkyl,—C₂-C₅alkenyl, —C₂-C₅alkynyl, —C₁-C₄fluoroalkyl, or —C₃-C₇cycloalkyl,the alkyl, alkenyl, alkylnyl, and cycloalkyl being optionallysubstituted with —OR⁶, —N(R⁶)₂, —C(O)OR⁶, —CN or —C(O)N(R⁶)₂; and R¹¹independently represents —H, —C₁-C₅alkyl, —C₂-C₅alkenyl, —C₂-C₅alkynyl,—C₁-C₄fluoroalkyl, or —C₃-C₇cycloalkyl, the alkyl, alkenyl, alkylnyl,and cycloalkyl being optionally substituted with —OR⁶, —N(R⁶)₂,—C(O)OR⁶, —CN or —C(O)N(R⁶)₂, or when two R¹¹ groups are attached to asame nitrogen atom, the two R¹¹ groups together with the nitrogen atomto which they are attached optionally form a 5-7-memberedheterocycloalkyl, the heterocycloalkyl optionally comprising one or morefurther heteroatom independently selected from —O—, —N(R³)—, —S—, —S(O)—and —SO₂—, provided that the compound of Formula I is other than:

or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein, in R2, the Aryl or Heteroaryl is substituted with one to threeR4 groups, each being the same or different.
 3. The method of claim 2,wherein, in R², the Aryl or the Heteroaryl is substituted with one ortwo R⁴ groups being the same or different.
 4. The method of claim 3,wherein when, in R², the Aryl or Heteroaryl is substituted with one R⁴group then the R⁴ group substitutes at position 2, 3, or 4, preferablyat position 2 or 4, or at position 4, or when the Aryl or Heteroaryl issubstituted with two R⁴ groups then the two R⁴ groups substitute a6-membered Aryl, then the two R⁴ groups are located at positions 2 and4, positions 3 and 4, positions 2 and 5, or at positions 2 and
 6. 5. Themethod of claim 3, wherein, in R²: ArylC(R³)═C(H)— is

wherein n is 2, and R⁴ is at positions 2 and 4, positions 2 and 5, orpositions 3 and 4; or Heteroaryl is

wherein n is 2, and R⁴ is at positions 5 and 7, X⁸ represents —NH—, —O—,or —S—, preferably —NH—, and X⁹ is —N═ or —CH═, preferably —CH═.
 6. Themethod of claim 1, wherein L¹ represents —CHR³—O—, —CH₂—NH—, —C(O)NH—,—CR⁶═CR⁶—, —CH₂—S—, or —CH₂—.
 7. The method of claim 1, wherein both X⁶and X⁷ represent —CR³═ or one of X⁶ and X⁷ represents —CR³═ and theother represents —NH═.
 8. The method of claim 1, wherein L² represents acovalent bond, —C(O)—, —C(R³)(OH)—, —O—, —S—, or —CHR³—O—.
 9. The methodof claim 1, wherein m represents 2, 3 or
 4. 10. The method of claim 1,wherein, in R¹, the heteroaryl is triazolyl, imidazolyl, pyrazolyl,pyridinyl, thiazolyl, pyrimidinyl, tetrazolyl, pyrazinyl, pyridazinyl,oxadiazolyl, or thiadiazolyl, each of which being optionally substitutedwith one or more R⁹, which are the same or different.
 11. The method ofclaim 1, wherein R¹ represents —N₃, —C(O)—N(H)—CH₂—C≡CH, —OH,—OC(O)—(N-morpholine), —O—C(O)—NMe₂, —O—C(O)—NEt₂, —N(H)C(O)H,—N(H)—C(O)O-tert-butyl; —N(H)—C(O)—(CH₂)₂OH, —N(H)—C(O)—(CH₂)₂OC(O)NMe₂,

wherein R¹³, R¹⁴ and R¹⁵ are independently H or R⁹, wherein R⁹ is asdefined in claim
 1. 12. The method of claim 1, wherein: X¹ is —N═, X² isa covalent bond, X³ is —C(R²)═, X⁴ is —O— or —S—, and X⁵ is —C(R³)═,wherein R² represents ArylC(R³)═C(H)—, HeteroarylC(R³)═C(H)—,Heteroaryl-, or

wherein: the Aryl group and the Heteroaryl group are optionallysubstituted with one to three R⁴ groups, which are the same ordifferent; n represents an integer from 0 to 3; X⁸ represents —NH—, or—O—; and X⁹ is —CH═; R³ independently represents —H, —C₁-C₅alkyl,—C₁-C₄fluoroalkyl, or —C₃-C₇cycloalkyl, the alkyl being optionallysubstituted with —OR⁶; R⁴ independently represents —F, —Cl, —Br, —I,—S(O)₂R⁵, —CN, —C(O)OR³, —NO₂, —OR³, —C(R³)₂OH, —N₃, or —R³; R⁵independently represents —C₁-C₅alkyl, —C₁-C₄fluoroalkyl, or—C₃-C₇cycloalkyl, the alkyl being optionally substituted with —OR⁶; R⁶is —H; L¹ represents —CHR³—O—, —CH₂—NH—, —CH═CH— or —CH₂—O—CH₂—; L²represents a covalent bond, —C(O)—, —CH(OH)—, or —S—; X⁶ and X⁷independently represent —CH═ or —N═; m is an integer from 1 to 4; and R¹represents heteroaryl or —N(R⁷)C(O)R⁷, the heteroaryl being optionallysubstituted with one or more R⁹, which are the same or different,wherein: R⁷ independently represents —C₁-C₅alkyl; R⁹ independentlyrepresents —C₁-C₆alkyl, —C₀-C₆alkyl-OR¹¹, —C₁-C₆alkyl-OC(O)N(R¹¹)₂,—C₀-C₆alkyl-C(O)N(R¹¹)₂, —C₁-C₆alkyl-N(R¹¹)S(O)₂R^(1′), or—Si(C₁-C₅alkyl)₃; R¹⁰ independently represents —C₁-C₅alkyl,—C₂-C₅alkynyl, or —C₃-C₇cycloalkyl, the alkyl, alkynyl, and cycloalkylbeing optionally substituted with —OR⁶; and R¹¹ independently represents—C₁-C₅alkyl, —C₂-C₅alkynyl, or —C₃-C₇cycloalkyl, the alkyl, alkynyl, andcycloalkyl being optionally substituted with —OR⁶, or when two R¹¹groups are attached to a same nitrogen atom, then the two R¹¹ groupstogether with the nitrogen atom to which they are attached optionallyform a 5 to 7-membered heterocycloalkyl, the heterocycloalkyl optionallycomprising one or more further heteroatom independently selected from—O—, —N(R³)—, —S—, —S(O)— and —SO₂—.
 13. The method of claim 1, wherein

represents

in which X¹ is —N═, X⁴ is —O— or —S—, and X⁵ is —CH═; wherein R²represents:

wherein R³ is H and n is 0; n is 3 and R⁴ is located on positions 3, 4,and 5 and is F in each occurrence; n is 2 and R⁴ is located on positions2 and 4 and is independently in each occurrence selected from F, Cl, Br,SO₂Me, CN, CO₂Me, NO₂, OMe, OCF₃, N₃, and CF₃; n is 2 and R⁴ is locatedon positions 3 and 4 and is F in each occurrence; or n is 1 and R⁴ islocated on position 2 or 4 and is selected from F, Cl, Br, CN, CO₂Me,NO₂, OH, OCF₃, CH₂OH, and CF₃;

wherein R³ is H and either n is 0, or n is 1 and R⁴ is located atposition 2 and is F, or

wherein X⁸ is —NH—, —O—, or —S—, and n is 0; n is 2 and R⁴ is located atpositions 5 and 7 and is F in each occurrence; or n is 1 and R⁴ islocated at position 5 or 6 and is F or NO₂; L¹ represents —CH₂—O—,—CH₂—O—CH₂—, —CH₂—NH—, or —CH═CH—; X⁶ and X⁷ each represent —CH═ or oneof X⁶ and X⁷ represents —CH═ and the other is —N═; L² represents acovalent bond and m is 4, or L² represents —C(O)—, —CH(OH)—, or —S— andm is 3, or L² represents —CH₂—O— and m is 2; and R¹ represents

wherein R¹⁴ is H and R¹³ is selected from H, methyl,—C₁-C₆alkyl-OC(O)N(R¹¹)₂, wherein the C₁-C₆alkyl is ethyl and eitherboth R¹¹ groups are methyl, or one R¹¹ group is isopropyl or cyclopentyland the other R¹¹ group is H, —C₁-C₆alkyl-OC(O)N(R¹¹)-L⁴—OR¹¹, whereinthe C₁-C₆alkyl is ethyl, N(R¹¹) is NH, L⁴ is ethyl, and —OR¹¹ is —OMe,—C₀-C₆alkyl-C(O)N(R¹¹)₂, wherein C₀-C₆alkyl is butyl and one R¹¹ groupis —CH₂—C≡CH, and the other R¹¹ group is H, —C₁-C₆alkyl-N(R¹¹)₂, whereinthe C₁-C₆alkyl is methyl and the two R¹¹ groups taken together with thenitrogen atom to which they are attached form a heterocycloalkyl whichis

and —SiMe₃;

wherein R¹³ and R¹⁴ are H and R¹⁵ is selected from: H,—C₁-C₆alkyl-OC(O)N(R¹¹)₂ wherein the C₁-C₆alkyl is ethyl and both R¹¹groups are methyl, and —C₁-C₆alkyl-N(R¹¹)S(O)₂R¹⁰, wherein theC₁-C₆alkyl is ethyl, R¹¹ is H, and R¹⁰ is Me or CF₃;

wherein R¹³ is H; or —N(R⁷)C(O)-L³—OC(O)N(R⁷)₂, wherein —N(R⁷)C(O)— is—NHC(O)—, L³ is ethylene, and N(R⁷)₂ is NH₂.
 14. The method of claim 1,wherein

represents

in which X¹ is —N═, X⁴ is —O—, and X⁵ is —CH═; wherein R² represents:

wherein R³ is H and n is 2 and R⁴ is located at positions 2 and 4 and isF in position 2 and F, Cl, Br, SO₂Me, CN, CO₂Me, NO₂, OCF₃, or CF₃ inposition 4; n is 2 and R⁴ is located at positions 3 and 4 and is F ineach occurrence; or n is 1 and R⁴ is located at position 4 and is CN orCO₂Me; or

wherein X⁸ is —NH— or —O—, and n is 2 and R⁴ is located at positions 5and 7 and is F in each occurrence; or n is 1 and R⁴ is located atposition 5 or 6 and is F or N₀₂; L¹ represents —CH₂—O—; X⁶ and X⁷ eachrepresent —CH═; L² represents a covalent bond and m is 4, or L²represents —C(O)—, —CH(OH)—, or —S— and m is 3; and R¹ represents

wherein R¹⁴ is H and R¹³ is H or —SiMe₃; or

wherein R¹³, R¹⁴ and R¹⁵ are each H.
 15. The method of claim 1, whereinsaid compound is selected from Compounds 2, 3B, 4 to 147, or apharmaceutically acceptable salt thereof.
 16. The method of claim 1,wherein said compound is selected from Compounds 10, 17, 19, 21, 23, 32,37 to 39, 41, 45, 47, 48, 53, 54, 61, 62, 71, 73, 81, 82, 97, 98, 102,105, 112, 116 to 124, 127, 128, 130, 131, 133, 138, 141, 144, and 147,or a pharmaceutically acceptable salt thereof.
 17. The method of claim1, wherein said compound is selected from Compounds 122, 124, 127, 128,130, 138, 141, 144, and 147, or a pharmaceutically acceptable saltthereof.
 18. The method of claim 1, wherein said AML is poor prognosisAML.
 19. The method of claim 1, wherein said AML comprises at least oneof the following features: (a) high level of expression of one or morehomeobox (HOX)-network genes; (b) high level of expression of one ormore of the genes depicted in Table 1; (c) low level of expression ofone or more of the genes depicted in Table 2; (d) one or more of thefollowing cytogenetic or molecular risk factor: intermediate cytogeneticrisk, Normal Karyotype (NK), mutated NPM1, mutated CEBPA, mutated FLT3,mutated DNA methylation genes, mutated RUNX1, mutated WT1, mutatedSRSF2, intermediate cytogenetic risk with abnormal karyotype(intern(abnK)), trisomy 8 (+8) and abnormal chr(5/7); and (e) aleukemicstem cell (LSC) frequency of at least about 1 LSC per 1×10⁶ total cells.20. The method of claim 19, wherein said AML comprises high level ofexpression of one or more HOX-network genes.